MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'Chemical Biology and Drug Design' source. Thu, 09 Feb 2012 14:32:01 +0100 http://www.medworm.com/index.php?rid=5673785&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01355.x This study demonstrates that the title cationic lipids have large potential to be efficient non‐viral gene vectors.© 2012 John Wiley & Sons A/S (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5673785 Thu, 09 Feb 2012 19:10:54 +0100 5673785 http://www.medworm.com/index.php?rid=5656249&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01352.x In the present study on the development of new anticonvulsants, sixteen new1‐(2‐(8‐(benzyloxy)quinolin‐2‐yl)‐1‐butyrylcyclopropyl)‐3‐substituted urea derivatives were synthesized and tested for anticonvulsant activity using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) screens, which are the most widely employed seizure models for early identification of candidate anticonvulsants. Their neurotoxicity were determined applying the rotorod test. Three compounds 7a, 7e and 7m showed promising anticonvulsant activities in both models employed for anticonvulsant evaluation. The most active compound 7e showed the MES‐induced seizures with ED50 value of 14.3 mg/kg and TD50 value of 434 mg/kg after intraperitoneally injection to mice, which provided com... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5656249 Fri, 03 Feb 2012 19:23:13 +0100 5656249 http://www.medworm.com/index.php?rid=5656251&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01350.x AbstractOur concept of Enzyme‐Mediated Cancer Imaging and Therapy aims to use radiolabeled compounds to target hydrolases over‐expressed on the extracellular surface of solid tumors. A data‐mining approach identified extracellular sulfatase 1 (SULF1) as an enzyme expressed on the surface of pancreatic cancer cells. We designed, synthesized, and characterized 2‐(2’‐sulfooxyphenyl)‐6‐iodo‐4‐(3H)‐quinazolinone (IQ2–S) as well as its radioiodinated form (125IQ2–S) as a prodrug with potential for hydrolysis by SULF1. IQ2–S was successfully docked in silico into three enzymes – homolog of SULF1, alkaline phosphatase, and prostatic acid phosphatase. The incubation of 125IQ2–S and 125IQ2–P with the three enzymes in solution confirms the docking results and enzyme ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5656251 Fri, 03 Feb 2012 05:00:00 +0100 5656251 http://www.medworm.com/index.php?rid=5656250&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01351.x AbstractThree‐dimensional quantitative structure activity relationship (3D‐QSAR) study has been carried out on the Escherichia coli DHFR inhibitors 2,4‐diamino‐5‐(substituted‐benzyl)pyrimidine derivatives to understand the structural features responsible for the improved potency. In order to construct highly predictive 3D‐QSAR models, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were used. The predicted models shows statistically significant cross validated and non‐cross validated correlation coefficient of and , respectively. The final 3D‐QSAR models were validated using structurally diverse test set compounds. Analysis of the contour maps generated from CoMFA and CoMSIA methods reveals that the subst... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5656250 Fri, 03 Feb 2012 05:00:00 +0100 5656250 http://www.medworm.com/index.php?rid=5656253&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01348.x AbstractHIV protease is a key enzyme to play a key role in the HIV‐1 replication cycle and control the maturation from HIV viruses to an infectious virion. HIV‐1 protease has become an important target for anti‐HIV‐1 drug development. Here we used molecular dynamics simulation to study the binding mode between mannitol derivatives and HIV‐1 protease. The results suggest that the most active compound (M35) has more stable hydrogen bonds and stable native contacts than the less active one (M17). These mannitol derivatives might have similar interaction mode with HIV‐1 protease. Then 3D‐QSAR was used to construct quantitative structure ‐ activity models. The cross‐validated q2 values are found as 0.728 and 0.611 for CoMFA and CoMSIA, respectively. And the non‐cross‐valid... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5656253 Thu, 02 Feb 2012 05:00:00 +0100 5656253 http://www.medworm.com/index.php?rid=5656252&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01349.x AbstractGlycogen phosphorylase is a molecular target for the design of potential hypoglycaemic agents. Structure based design pinpointed that the 3’‐position of glucopyranose equipped with a suitable group has the potential to form interactions with enzyme’s cofactor, PLP, thus enhancing the inhibitory potency. Hence, we have investigated the binding of two ligands, 1‐(β‐D‐glucopyranosyl)5‐fluorouracil (GlcFU) and its 3’–CH2OH glucopyranose derivative. Both ligands were found to be low μM inhibitors with Ki values of 7.9 and 27.1 μM, respectively. X‐ray crystallography revealed that the 3’–CH2OH glucopyranose substituent is indeed involved in additional molecular interactions with the PLP γ‐phosphate compared to GlcFU. However it is 3.4 times less potent. To e... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5656252 Thu, 02 Feb 2012 05:00:00 +0100 5656252 http://www.medworm.com/index.php?rid=5656255&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01328.x AbstractFour novel linear non‐peptidic HIV‐1 protease inhibitors derived from 2,5‐diamino‐1,6‐diphenyl‐3‐hexanol were synthesized and characterized. All of them exhibit tight binding to HIV‐1 protease, with inhibition constants Ki in the range 20 pM – 5 nM. The investigated inhibitors were crystallized and their crystal structures were determined by X‐ray diffraction. In all cases, the conformations found in the crystalline state differ significantly from the conformations obtained by computational docking of the inhibitor in the binding cleft of native HIV‐1 protease.Due to prevalence of hydrophobic substituents in all these inhibitors, the conformational mobility in water solution is restricted to their compact forms. The spectrum of low energy conformations in solu... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5656255 Wed, 01 Feb 2012 05:00:00 +0100 5656255 http://www.medworm.com/index.php?rid=5656254&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01329.x AbstractSeveral experiments have been performed to test DNA binding drugs to cure Leishmania infection. However, there are no details of pharmacoinformatics study. Herein, we have selected a good number of compounds from experimentally verified studies and performed a comparative analysis based on Pharmacoinformatics techniques. In silico docking study were performed to observe the molecular level interactions of these known ligands with the DNA receptor by automated computational docking using Glide. A comparison between the calculated interaction energies and in silico ADME/T study was made. In agreement of drug likeness rules, our study suggests that, Seco‐hydroxy‐aza‐CBI‐TMI (compound 4b; GScore: ‐12.058) is a potential molecule for targeting the DNA to cure Leishmaniasis.© ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5656254 Wed, 01 Feb 2012 05:00:00 +0100 5656254 http://www.medworm.com/index.php?rid=5635261&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01347.x AbstractOur approach was to synthesize and examine the antioxidant properties of some new 2‐[2‐(4‐chlorophenyl)benzimidazole‐1‐yl]‐N‐(2‐arylmethyleneamino) acetamide (1‐18) and 2‐[2‐(4‐chlorophenyl)benzimidazole‐1‐yl]‐N‐(4‐oxo‐2‐aryl‐thiazolidine‐3‐yl)acetamide (1t‐18t) derivatives. Their in vitro effects on rat liver microsomal NADPH‐dependent lipid peroxidation levels (LP assay) and microsomal ethoxyresorufin O‐deethylase activities (EROD assay) were determined. The free radical scavenging properties of the compounds were also examined in vitro determining the interaction of 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) free radical. The compounds showed significant effects in the above tests.© 2012 John Wiley & Sons A/S (Source: Chemic... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5635261 Fri, 27 Jan 2012 19:27:38 +0100 5635261 http://www.medworm.com/index.php?rid=5635265&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01343.x Abstractthe synthesis of a series of cyclooctadiene anhydrides, analogues of the natural compound zopfiellin, was performed in order to assay their in vitro and in vivo antifungal activity on a set of plant pathogenic fungi. Most of the synthesised compounds possessed a broad spectrum of activity. In particular the anhydrides 2 and 5a were very effective against the Oomycete diseases such as Phytophthora infestans and Pythium ultimum, reaching a level of activity well comparable with that of commercial fungicides in use. Preliminary in vivo evaluation of their protectant activity are also reported.© 2012 John Wiley & Sons A/S (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5635265 Fri, 27 Jan 2012 05:00:00 +0100 5635265 http://www.medworm.com/index.php?rid=5635264&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01344.x The diversity‐oriented chemistry synthesis together with the random screening approach has permitted the discovery and optimization of novel antiviral lead compounds. In this paper, a series of novel 5‐substituted‐2‐(4‐substituted phenyl)‐1,3‐benzoxazoles was synthesized and evaluated for their in vitro anti‐influenza A virus (IFV‐A) and anti‐influenza B virus (IFV‐B) activity. The activity was monitored by the MTS assay in the Madin‐Darby canine kidney (MDCK) cells. Compound 7h showed excellent inhibitory activity and selective index against A/H3N2 (EC50 = 37.03 μM, SI>5), which were all higher than that of the reference drug Oseltamivir (EC50 >59.00 μM, SI>1). However, no compound displays inhibitory activity against influenza B virus.© 2012 John Wiley... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5635264 Fri, 27 Jan 2012 05:00:00 +0100 5635264 http://www.medworm.com/index.php?rid=5635263&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01345.x AbstractDihydroperoxides and tetraoxanes derived from symmetrically substituted bis(arylmethyl)acetones were synthesized in modest to good yields using several methods. Three of these compounds exhibit important in vitro antimalarial activity (1.0 μM ≤ IC50≤ 5.0 μM) against blood forms of the human malaria parasite Plasmodium falciparum.© 2012 John Wiley & Sons A/S (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5635263 Fri, 27 Jan 2012 05:00:00 +0100 5635263 http://www.medworm.com/index.php?rid=5635262&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01346.x A series of N‐nitrourea derivatives bearing various aryl substituents were conveniently obtained via three steps including nitration, carbamic chlorination and aminolysis reactions. The structures of all newly synthesized compounds were characterized and confirmed by IR, 1H NMR, MS and elemental analysis. The preliminary bioassays indicate that five compounds possess sufficient fungicidal activity against Rhizoctonia solani. Structure‐activity relationship (SAR) is also discussed based on the experimental data, and the further quantitative structure‐activity relationship (QSAR) were analyzed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA).© 2012 John Wiley & Sons A/S (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5635262 Fri, 27 Jan 2012 05:00:00 +0100 5635262 http://www.medworm.com/index.php?rid=5624584&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01342.x Pseudomonas aeruginosa (P. aeruginosa) colonize on most wounds and live as biofilm which causes antibiotic resistance and wounds unhealed. To investigate the effects of 5‐substituted 3,4‐dihalo‐5H‐furan‐2‐one compounds on biofilm formation of P. aeruginosa, a set of 5‐(aryl‐1’‐hydroxy‐methyl)‐ or 5‐(aryl‐2‐methylene)‐ 3,4‐dihalo‐5H‐furan‐2‐one compounds were designed and synthesized. Their inhibitory activities on biofilm formation of P. aeruginosa were studied by MIC assay, quantitative analysis of biofilm inhibition and observation of biofilm formation with SEM. It was found that compounds 2i, 3f, 3i showed remarkable effects of biofilm formation inhibition on P. aeruginosa. Furthermore, molecular docking was performed to identify the key structu... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5624584 Tue, 24 Jan 2012 19:44:29 +0100 5624584 http://www.medworm.com/index.php?rid=5624588&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01339.x AbstractCathepsin D (CatD) is a major component of lysosomes and plays a major role in catabolism and degenerative diseases. The quantitative structure‐activity relationship study was used to explore the critical chemical features of CatD inhibitors. Top ten hypotheses were built based on 36 known CatD inhibitors using HypoGen/Discovery Studio v2.5. The best hypothesis, Hypo1 consists of three hydrophobic, one hydrogen bond acceptor lipid, and one hydrogen bond acceptor features. The selected Hypo1 model was cross validated using Fischer’s randomization method to identify the strong correlation between experimental and predicted activity value as well as the test set and decoy sets used to validate its predictability. Moreover, the best hypothesis was used as a 3D query in virtual scre... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5624588 Mon, 23 Jan 2012 05:00:00 +0100 5624588 http://www.medworm.com/index.php?rid=5624587&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01340.x We present experimental evidence that colchicine and combretastatin A‐4 bind to γ‐tubulin, which are to our knowledge the first drug‐like compounds known to interact with γ‐tubulin. Molecular dynamics (MD) simulations and docking studies were used to analyze the hypothesized γ‐tubulin binding domain of these compounds. The suitability of the potential binding modes were evaluated, and suggest the subsequent rational design of novel targeted inhibitors of γ‐tubulin.© 2012 John Wiley & Sons A/S (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5624587 Mon, 23 Jan 2012 05:00:00 +0100 5624587 http://www.medworm.com/index.php?rid=5624586&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01338.x AbstractReceptor dependent four‐dimensional quantitative structure‐activity relationship (4D‐QSAR) studies were applied on a series of 21 peptides reversible inhibitors of Trypanosoma cruzi Trypanothione Reductase (TR) (McKie et al. Amino Acids 2001, 20:145). The RD‐4D‐QSAR (Pan, Tseng, Hopfinger, J. Chem. Inform. Comp. Sci., 2003, 43:1591) approach can evaluate multiple conformations from Molecular Dynamics Simulation and several superposition structure alignments inside a box composed by unitary cubic cells. The descriptors are the occupancy frequency of the atoms types inside the grid cells. We could develop 3D‐QSAR models that were highly predictive (q2 above 0.71). The 3D‐QSAR models can be visualized as a spatial map of atom types that are important on the comprehension... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5624586 Mon, 23 Jan 2012 05:00:00 +0100 5624586 http://www.medworm.com/index.php?rid=5624585&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01341.x AbstractOne pharmacophore model and three quantitative structure‐activity relationship (QSAR) models were developed on a series of benzimidazole and imidazole inhibitors of histone deacetylase 2 (HDAC2). The goodness of hit (GH) score value of the best pharmacophore model was 0.756, which indicated that it is reliable to be used for virtual screening. The built pharmacophore model was used to search the NCI database. The hit compounds were subjected to molecular docking. The results showed that twenty‐five compounds had high scores and strong interactions with HDAC2. In 3D‐QSAR studies, good predictive models were obtained by using CoMFA, CoMSIA and Topomer CoMFA. Some putative active compounds were proposed based on compound No. 41. Twenty six compounds had high scores and good inte... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5624585 Mon, 23 Jan 2012 05:00:00 +0100 5624585 http://www.medworm.com/index.php?rid=5616861&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01299.x Neuraminidase (NA) is a major glycoprotein of influenza virus which is essential for viral infection. It offers a potential target for antiviral drug development. To develop potent NA inhibitors, pharmacophore models were generated by genetic algorithm with linear assignment for hypermolecular alignment of data sets. 3D‐QSAR studies were carried out on 49 molecules. Both comparative molecular field analysis (q2 = 0.720 and r2 = 0.947) and comparative molecular similarity indices analysis (q2 = 0.644 and r2 = 0.885) yielded reasonable results. A preliminary pharmacokinetic profile of these neuraminidase inhibitors was predicted using Volsurf module.3D‐QSAR studies of a series of pyrrolidine neuraminidase inhibitors were carried out to understand the structural basis for ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5616861 Sat, 21 Jan 2012 19:14:42 +0100 5616861 http://www.medworm.com/index.php?rid=5616860&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01300.x Disruption of glycosylphosphatidylinositol biosynthesis is genetically and chemically validated as a drug target against the protozoan parasite Trypanosoma brucei, the causative agent of African sleeping sickness. The N‐acetylglucosamine‐phosphatidylinositol de‐N‐acetylase (deNAc) is a zinc metalloenzyme responsible for the second step of glycosylphosphatidylinositol biosynthesis. We recently reported the synthesis of eight deoxy‐2‐C‐branched monosaccharides containing carboxylic acid, hydroxamic acid, or N‐hydroxyurea substituents at the C2 position that may act as zinc‐binding groups. Here, we describe the synthesis of a glucocyclitol‐phospholipid incorporating a hydroxamic acid moiety and report the biochemical evaluation of the monosaccharides and the glucocyclitol�... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5616860 Sat, 21 Jan 2012 19:14:29 +0100 5616860 http://www.medworm.com/index.php?rid=5616859&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01320.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5616859 Sat, 21 Jan 2012 19:14:21 +0100 5616859 http://www.medworm.com/index.php?rid=5616854&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01337.x AbstractThe leader peptide of a recombinant manganese superoxide dismutase (rMnSOD‐Lp) acts as a molecular carrier. Clonogenic tests on normal (MRC‐5) and endometrial adeno‐carcinoma cells (HTB‐112) were carried out in the presence of rMnSOD‐Lp, cisplatin alone (CC) or cisplatin conjugated to the rMnSOD‐Lp (rMnSOD‐Lp‐CC). The platinum delivered into the cells was measured by atomic spectrophotometric absorbance. The treatments on tumor and normal cells were finally evaluated by LM and TM microscopy. Tumor cell death in the case of 0.5 μM cisplatin on its own was minimal, while in the presence of 0.5 μM rMnSOD‐Lp‐CC, no tumor cells survived. Atomic absorbance analysis showed that rMnSOD‐Lp‐CC delivered approximately 4 times more cisplatin into HTB�... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5616854 Sat, 21 Jan 2012 19:13:08 +0100 5616854 http://www.medworm.com/index.php?rid=5616858&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01333.x Six lycorine derivatives were prepared, characterized and evaluated for their in vitro anti‐Trichomonas vaginalis activity. Compounds bearing an acetyl (2), lauroyl (3), benzoyl (4 and 5) and p‐nitrobenzoyl (6 and 7) groups were synthesized. The best activity was achieved with lycorine esterified at C‐2 position with lauroyl group. Preliminary structure‐activity relationship points that unprotected OH group at C‐1 and C‐2 is not necessary to the antiparasitic activity and none derivative was less active than lycorine. The lycorine structural requisites required to kill this amitochondriate cell seem to be different in comparison to the derivatives most active against other parasites and tumor cell lines, both mitochondriated cells. This result is an important contribution with ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5616858 Thu, 19 Jan 2012 05:00:00 +0100 5616858 http://www.medworm.com/index.php?rid=5616857&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01334.x P‐Type ATPases constitute a ubiquitous superfamily of cation transport enzymes, responsible for carrying out actions of paramount importance in biology such as ion transport, and expulsion of toxic ions from cells etc. The harmonized toggling of gates in the extra and intracellular domains explains the phenomenon of specific cation binding in selective physiological states. A quantitative understanding of the fundamental aspects of ion transport mechanism and regulation of P‐Type ATPases require detailed knowledge of thermodynamical, structural and functional properties. Computational studies have made significant contributions to our understanding of biological ion pumps. Various 3D structures of Ca2+‐ATPase between E1‐E2 transition states has given a impetus to the theorists to w... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5616857 Thu, 19 Jan 2012 05:00:00 +0100 5616857 http://www.medworm.com/index.php?rid=5616856&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01335.x DFT calculation results demonstrated that the efficiency of the acid‐catalyzed hydrolysis of Kirby’s acid amides 1‐15 is strongly dependent on the substitution on the C‐C double bond and the nature of the amide N‐alkyl group. Further, the results established that while in the gas phase the hydrolysis rate‐limiting step is the tetrahedral intermediate formation in polar solvents such as water the rate‐limiting step could be either the formation or the collapse of the tetrahedral intermediate depending on the substitution on the C‐C double bond and on the amide nitrogen substituent. Based on a linear correlation between the calculated and experimental effective molarities (EM) the study on the systems reported herein could provide a good basis for designing prodrug systems th... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5616856 Thu, 19 Jan 2012 05:00:00 +0100 5616856 http://www.medworm.com/index.php?rid=5616855&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01336.x AbstractThe prevalence of allergic disease is increasing dramatically in the developed world. Studies of allergic diseases have clearly demonstrated that histamine plays an important role in the pathogenesis of the early‐phase allergic response. Histamine effects are mediated by H1, H2, H3 and H4 receptors. The presence of the Histamine H4 receptors on leukocytes and mast cells suggests that the new histamine receptor H4 plays an important role in the modulation of the immune system. Thus Histamine H4 receptor is an attractive target for anti‐allergic therapy. In our present study we have generated a Histamine H4 receptor model using I‐TASSER based on human B2‐adrenergic G protein‐coupled receptor. Structurally similar compounds of the three known antagonists JNJ777120, Thioperam... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5616855 Thu, 19 Jan 2012 05:00:00 +0100 5616855 http://www.medworm.com/index.php?rid=5603782&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01331.x AbstractA series of new aurantiamide acetate analogues were synthesized by modifying its N‐terminal substitution and the amino acid residue. The structure of all these compounds was established on the basis of analytical and spectral studies. All the new derivatives were evaluated in vivo for their analgesic activity by tail flick method in mice and anti‐inflammatory activity against carrageenan induced oedema in albino rats at different doses (25, 50 and 100 mg/kg body weight). All the compounds exhibited significant pharmacological activity with no ulcerogenic liability. In particular, pentapeptides and tricosamers (30 amino acids) containing analogues have demonstrated high potency than the reference standards. These compounds hold promise for further development.© 2012 John Wiley ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5603782 Wed, 18 Jan 2012 20:10:12 +0100 5603782 http://www.medworm.com/index.php?rid=5603784&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01332.x AbstractA series of novel stilbene derivatives containing ligustrazinyl moiety was designed, synthesized, and assayed for their protective effects on damaged endothelial cells. The results showed that most ligustrazinyl stilbene derivatives exhibited high protective effects on the human umbilical vascular endothelial cells (HUVECs) damaged by hydrogen peroxide in comparison with Ligustrazine. The stilbene derivatives A6, A9, A11, A21, A24, A25 and A27 exhibited high potency with low EC50 values ranged from 0.0249 μM to 0.0898 mM. Compound A27 displayed EC50 0.0249μM, which is 30000 times higher than that of Ligustrazine, presenting a most promising lead for further investigation. Structure‐activity relationships were briefly discussed.© 2012 John Wiley & Sons A/S (Source: Chemical... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5603784 Tue, 17 Jan 2012 05:00:00 +0100 5603784 http://www.medworm.com/index.php?rid=5603783&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01330.x AbstractDocking studies of pyrrolidine derivatives indicated that Trp178, Arg371 and Tyr406 were the key residues in the active pocket of influenza neuraminidase (NA). Hydrogen bond and electrostatic factors mainly influenced interactions between pyrrolidine derivatives and NA. Moreover, there was a significant correlation between binding affinity (total scores) and the experimental pIC50. Meanwhile, 3D‐QSAR models of 87 pyrrolidine derivatives were developed to understand chemical‐biological interactions governing their activities toward NA. Furthermore, R2, Q2, R2test and Q2ext of the models were from 0.731 to 0.830, from 0.560 to 0.611, from 0.762 to 0.875, and from 0.649 to 0.856, respectively. QSAR modeling results elucidated that hydrogen bonds and electrostatic factors highly co... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5603783 Tue, 17 Jan 2012 05:00:00 +0100 5603783 http://www.medworm.com/index.php?rid=5603786&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01323.x AbstractChalcone derivatives on an estradiol framework were evaluated for their ability to inhibit the growth and development of the malaria parasite Plasmodium falciparum. Out of twelve steroidal chalcones and one indanone derivative studied, three were found to have 50% growth inhibitory concentration less than 5 μM and minimum inhibitory concentration for parasite development from ring to schizont stage as ≤ 20 μM with best activity for gallic acid based chalcone derivative 1 as 2.07 μM and 10 μM, respectively. Two of the active derivatives 1 and 10 did not exhibit cytotoxicity against vero cells as evident by the good selectivity ratio. Study of structure‐activity relationship indicated that increasing substitution in the benzoyl ring enhanced antiplasmodial activity. Hemozoin ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5603786 Mon, 16 Jan 2012 05:00:00 +0100 5603786 http://www.medworm.com/index.php?rid=5603785&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01325.x In this study, we sought to understand the inter‐molecular physical interactions in the FGF21/FGFR/β‐Klotho complex by deleting key regions in FGFR1c or FGF21. Deletion of the D1 and the D1‐D2 linker (the D1/linker region) from FGFR1c led to β‐Klotho‐independent receptor activation by FGF21, suggesting that there may be a direct interaction between FGF21 and the D1/linker region‐deficient FGFR1c. Consistent with this, the extracellular portion of FGFR1c lacking the D1/linker region blocked FGF21 action in a reporter assay, presumably by binding to and sequestering FGF21 from acting on cell surface receptor complex. In addition, the D1/linker region‐deficient FGFR1c had enhanced interaction with β‐Klotho. Further, we demonstrated that deletion of the D1/linker region enha... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5603785 Mon, 16 Jan 2012 05:00:00 +0100 5603785 http://www.medworm.com/index.php?rid=5592823&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01327.x Methods for the preparation of various aminomethylenebisphosphonates (BPs) were developed. The required BPs were obtained by applying tetraethyl methylenebisphosphonate reagent to different types of oxazinones and the relevant Schiff base derivatives. Based on the prediction results (PASS program), we further estimated the sister chromatid exchanges (SCE) frequency and proliferation rate index (PRI) values of human lymphocyte cultures after the administration of four newly‐synthesized bisphosphonates in order to evaluate their cytotoxic/cytostatic and possible antineoplastic potency. The results showed that all four BPs cause a dose‐dependent increase of SCE frequency, followed by a decrease of PRI in both experiments compared to the control.© 2012 John Wiley & Sons A/S (Source: C... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5592823 Sun, 15 Jan 2012 08:29:52 +0100 5592823 http://www.medworm.com/index.php?rid=5656256&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01321.x In conclusion, our finding will let us to design effective chemotherapy against malaria parasite exploiting PFD0975w as a drug target.Molecular model of PfRIO‐2 has subtle but significant difference from HuRIO‐2 to exploit for drug development. This is the first structural reports to identify peptide binding regions on RIO‐2 kinase. Our results are first attempt to characterize and validate atypical protein kinase, PFD0975w as drug target to develop drug against malaria. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5656256 Tue, 10 Jan 2012 05:00:00 +0100 5656256 http://www.medworm.com/index.php?rid=5592827&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01321.x In conclusion, our finding will let us to design effective chemotherapy against malaria parasite exploiting PFD0975w as a drug target.© 2012 John Wiley & Sons A/S (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5592827 Tue, 10 Jan 2012 05:00:00 +0100 5592827 http://www.medworm.com/index.php?rid=5592826&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01322.x AbstractThe design and optimization of p53‐MDM2 interaction inhibitors has attracted a great deal of interest in development of new anticancer agents. An systematical 2D‐QSAR studies on ninety‐eight isoindolinone‐based p53‐MDM2 interaction inhibitors were carried out using linear and the non‐linear mathematical methods. At first, an forward stepwise‐multiple linear regression model (FS‐MLR) was proposed with reasonable statistical parameters (Rtrain2 = 0.881, Qloo2 = 0.847, Rtest2 = 0.854). Then, enhanced replacement method ‐ multiple linear regression (ERM‐MLR) and support vector machine regression (SVMR) were applied to set up more accurate models (ERM‐MLR: Rtrain2 = 0.914, Qloo2 = 0.894 and Rtest2 = 0.903; SVMR: Rtrain2 = 0.924, Qloo2 = 0.920 and Rtest2 of 0.874). ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5592826 Tue, 10 Jan 2012 05:00:00 +0100 5592826 http://www.medworm.com/index.php?rid=5592825&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01324.x We report the computational and rational design of new generations of several tryptophan‐rich peptides from the compstatin family. The binding efficacy of the peptides has been tested using extensive molecular dynamics‐based structural and physicochemical analysis, using 32 atomic‐detail trajectories in explicit water for 22 peptides bound to human, rat, or mouse target protein C3, to a total of 257 nanoseconds. The criteria for the new designs are: (i) optimization for high binding affinity and for the balance between hydrophobicity and polarity to improve solubility compared to known compstatin analogs; and (ii) development of dual specificity anti–human‐rat/mouse C3 analogs, which is important for use in animal models for disease, given the species specificity of known compsta... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5592825 Tue, 10 Jan 2012 05:00:00 +0100 5592825 http://www.medworm.com/index.php?rid=5592824&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01326.x The objective of this study is to identify novel HIV‐1 integrase (IN) inhibitors. Here shape based screening and QSAR have been successfully implemented to identify the novel inhibitors for HIV‐1 IN and in silico validation is done by docking studies. The 2D QSAR model of benzodithiazine derivatives was built using Genetic Function Approximation (GFA) method with good internal (cross‐validated r2 = 0.852) and external prediction (r2pred = 0.650). Best docking pose of highly active molecule of the benzodithiazine derivatives was used as template for shape based screening of ZINC database. Toxicity prediction was also performed using DEREK program to filter non‐toxic molecules. Inhibitory activities of screened non‐toxic molecules were predicted using derived QSAR models. Active, n... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5592824 Tue, 10 Jan 2012 05:00:00 +0100 5592824 http://www.medworm.com/index.php?rid=5576553&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01319.x AbstractA novel series of 2‐(4‐(2‐amino‐6‐(4‐ substituted phenyl) pyrimidin‐4‐yl)‐2‐substituted phenoxy) acetic acid derivatives were efficiently synthesized. The synthesized compounds were evaluated for their in vivo hypolipidemic activity, using high fat diet induced hyperlipidemia in rats. Some of these compounds showed significant anti‐hyperlipidemic activity.© 2012 John Wiley & Sons A/S (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5576553 Mon, 09 Jan 2012 23:02:56 +0100 5576553 http://www.medworm.com/index.php?rid=5643711&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01319.x A novel series of 2‐(4‐(2‐amino‐6‐(4‐substituted phenyl) pyrimidin‐4‐yl)‐2‐substituted phenoxy) acetic acid derivatives were efficiently synthesized. The synthesized compounds were evaluated for their in vivo hypolipidemic activity, using high‐fat‐diet‐induced hyperlipidemia in rats. Some of these compounds showed significant antihyperlipidemic activity.A novel series of 2‐(4‐(2‐amino‐6‐(4‐ substituted phenyl) pyrimidin‐4‐yl)‐2‐substituted phenoxy) acetic acid derivatives were efficiently synthesized. The synthesized compounds were evaluated for their in vivo hypolipidemic activity, using high fat diet induced hyperlipidemia. Some of these compounds showed significant anti‐hyperlipidemic activity. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5643711 Sat, 07 Jan 2012 05:00:00 +0100 5643711 http://www.medworm.com/index.php?rid=5576555&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01317.x AbstractN‐methyl‐D‐aspartate (NMDA) receptors belong to the family of ligand‐gated ion channels and are important for synaptic plasticity and memory function. The NMDA receptor consists of a voltage‐dependent channel permeable to Ca2+ and Na+. In Alzheimer’s disease, neuronal degeneration is thought to cause an excessive release of glutamate to the extracellular space, which may in turn mediate prolonged stimulation of the NMDA receptor complex, and, as a consequence, excessive calcium influx into neuronal cells leading to subsequent cell death. This process is called glutamate‐induced excitotoxicity and its inhibition may present an effective antidementive therapy. We found that 1‐benzyl‐1,2,3,4‐tetrahydro‐β‐carboline (1a) blocked NMDA receptor mediated, glutamate... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5576555 Sat, 07 Jan 2012 05:00:00 +0100 5576555 http://www.medworm.com/index.php?rid=5576554&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2012.01318.x In this study, AVP analogues modified with proline derivatives: indoline‐2‐carboxylic acid, Ica; (2S,4R)‐4‐(naphthalene‐2‐ylmethyl)pyrrolidine‐2‐carboxylic acid, Nmp; (2S,4S)‐4‐ aminopyroglutamic acid, APy and (2R,4S)‐4‐aminopyroglutamic acid, Apy, were examined using NMR spectroscopy and molecular modelling methods. The results have shown that Ica is involved in the formation of the cis peptide bond. Moreover, it reduces to a great extent the conformational flexibility of the peptide. In turn, incorporation of (2S,4R)‐Nmp stabilizes the backbone conformation, which is heavily influenced by the pyrrolidine ring. However, the aromatic part of the Nmp side chain exhibits a high degree of conformational freedom. With analogues IV and V, introduction of the 4‐aminop... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5576554 Sat, 07 Jan 2012 05:00:00 +0100 5576554 http://www.medworm.com/index.php?rid=5568646&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01265.x Oxovanadium (IV) complexes of N,N′‐bispyridoxyl‐5, 5′‐bis (phosphate) ethylenediimine (L1) and N,N′‐bis(pyridoxyl)‐5,5′‐bis(phosphate)‐1′′‐(p‐nitrobenzyl)ethylenediimine (L2) were synthesized by condensation of optically active C‐substituted diamines and pyridoxal‐5‐phosphate. Oxovanadium (IV) complexes derived from L1 and L2 were evaluated as DNA cleavage agent (cleavage of supercoiled plasmid pBR322 DNA). Interestingly, both the oxovanadium (IV) complexes exhibited DNA nuclease activity, and the extent of oxidation of DNA by these vanadyl complexes was superior to VOSO4. The significant reduction in primary tumor and increased delay in tumor growth of 15 days was seen in the tumor regression analysis with oxovanadium (IV) complex of L1. With the prel... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5568646 Sat, 07 Jan 2012 01:38:48 +0100 5568646 http://www.medworm.com/index.php?rid=5568645&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01292.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5568645 Sat, 07 Jan 2012 01:38:32 +0100 5568645 http://www.medworm.com/index.php?rid=5549620&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01316.x AbstractNovel nalidixic acid based 1,3,4‐thia(oxa)diazoles, their thio ethers, sulfones, bis mercapto and Mannich bases were synthesized and characterized by IR, 1H NMR, 13C NMR, and elemental analysis. These compounds were evaluated for their antibacterial activity against two gram‐positive and three gram‐negative bacteria. The preliminary bioassay showed that most of the compounds had better antibacterial activity than the parent compounds, 1,3,4‐thia(oxa)diazoles, at the dosage 50 μg/mL towards five test bacteria. Four mannich bases of nalidixic based 1,3,4‐thiadiazole exhibited maximum antibacterial activity against Bacillus subtilis, Klebsiella pneumoniae and Pseudomonas aeruginosa with minimum inhibitory concentration in the range of 6.25 ‐125 μg/mL.© 2011 John Wiley &... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5549620 Thu, 29 Dec 2011 11:47:50 +0100 5549620 http://www.medworm.com/index.php?rid=5656257&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01316.x Novel nalidixic acid‐based 1,3,4‐thia(oxa)diazoles, their thio ethers, sulfones, bis mercapto, and Mannich bases were synthesized and characterized by Infrared spectra, 1H NMR, 13C NMR, and elemental analysis. These compounds were evaluated for their antibacterial activity against two Gram‐positive and three Gram‐negative bacteria. The preliminary bioassay showed that most of the compounds had better antibacterial activity than the parent compounds, 1,3,4‐thia(oxa)diazoles, at the dosage 50 μg/mL toward five test bacteria. Four Mannich bases of nalidixic acid‐based 1,3,4‐thiadiazole exhibited maximum antibacterial activity against Bacillus subtilis, Klebsiella pneumoniae, and Pseudomonas aeruginosa with minimum inhibitory concentration in the range of 6.25–125 μg/mL.N... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5656257 Wed, 28 Dec 2011 05:00:00 +0100 5656257 http://www.medworm.com/index.php?rid=5533086&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01315.x AbstractTo understand the protein transduction domain (PTD)‐mediated protein transduction behavior and to explore its potential in deliverying biopharmaceutic drugs, we prepared four TAT‐EGFP conjugates : TAT(+)‐EGFP, TAT(‐)‐EGFP, EGFP‐TAT(+) and EGFP‐TAT(‐), where TAT(+) and TAT(‐) represent the original and the reversed TAT sequence, respectively. These four TAT‐EGFP conjugates were incubated with HeLa and PC12 cells for in vitro study as well as injected intraperitoneally to mice for in vivo study. Flow cytometric results showed that four TAT‐EGFP conjugates were able to traverse HeLa and PC12 cells with almost equal transduction efficiency. The in vivo study showed that the TAT‐EGFP conjugates could be delivered into different organs of mice with different trans... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5533086 Fri, 23 Dec 2011 08:20:47 +0100 5533086 http://www.medworm.com/index.php?rid=5533088&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01313.x This study demonstrates that careful use of selective side‐chain residue flexibility can improve AutoDock Vina docking score accuracy, without a significant increase in processing time. This methodology can be a valuable tool in drug design projects using VEGFR‐2 but will also probably be useful if applied to other protein targets.© 2011 John Wiley & Sons A/S (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5533088 Wed, 21 Dec 2011 05:00:00 +0100 5533088 http://www.medworm.com/index.php?rid=5533087&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01314.x Abstractprotein acetylation has early emerged as a major posttranslational modification for histones, and was recently found to be involved in a variety of biological events such enzymatic activation and signal transduction. Traditional notion about the physicochemical effects associated with protein acetylation is mainly due to its presence capable of neutralizing positively charged protein system, while diverse noncovalent interactions arising from the acetylation are largely ignored and has never been investigated systematically. In the current work, we perform a comprehensive examination of the geometrical profile and energetic landscape of such acetylation‐related noncovalent interactions in protein context by using a combination of high‐level ab initio calculations, crystal struc... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5533087 Wed, 21 Dec 2011 05:00:00 +0100 5533087 http://www.medworm.com/index.php?rid=5520217&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01273.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5520217 Tue, 20 Dec 2011 07:26:08 +0100 5520217 http://www.medworm.com/index.php?rid=5520216&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01272.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5520216 Tue, 20 Dec 2011 07:26:06 +0100 5520216 http://www.medworm.com/index.php?rid=5520209&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01312.x AbstractMany proteases are produced as zymogens bearing the N‐terminal proregions acting both as intramolecular chaperones and as protease inhibitors. The latter role of the proregions as potent and specific inhibitors of their associated protease has been demonstrated in various peptidases and thereby has been targeted for alternative pest control. Here, we isolated amino acid sequence of Plutella xylostella (PX) midgut trypsin from larvae of diamondback moth and tested in silico for its inhibitory activity towards propeptide models using computational modeling and docking. The propeptide models (AAAPGHR, AAAPGRR, AAAPGKR, AAPGHRI, APGHRIV, PGHRIVG, AAAAPGH and AAAAAPG) were designed based on histidine mutated and frame‐shifted modifications of the 7 amino acid proregion (AAAPGHR) of ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5520209 Tue, 20 Dec 2011 07:24:48 +0100 5520209 http://www.medworm.com/index.php?rid=5643713&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01309.x Linear and nonlinear quantitative structure activity relationship models for predicting the inhibitory activities of sulfonamides toward different carbonic anhydrase isozymes were developed based on multilinear regression, principal component‐artificial neural network and correlation ranking‐principal component analysis, to identify a set of structurally based numerical descriptors. Multilinear regression was used to build linear quantitative structure activity relationship models using 53 compounds with their quantum chemical descriptors. For each type of isozyme, separate quantitative structure activity relationship models were obtained. It was found that the hydration energy plays a significant role in the binding of ligands to the CAI isozyme, whereas the presence of five‐membere... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5643713 Mon, 19 Dec 2011 05:00:00 +0100 5643713 http://www.medworm.com/index.php?rid=5643712&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01311.x A series of dehydroepiandrosterone derivatives containing an acid ester was synthesized and evaluated for their antitumor activity on ES‐2, A549, and HepG2 cells by the MTT assay. Most compounds showed antitumor activity, while compounds 1c, 2i, and 2o exhibited more potential inhibitory effects compared with dehydroepiandrosterone on ES‐2 cells, A549 cells, and HepG2 cells, respectively.A series of dehydroepiandrosterone derivatives containing an acid ester were synthesized and evaluated the antitumor activity on ES‐2, A549 and HepG2 cells. Most compounds showed antitumor activity, especially compound 2i on ES‐2 cells, 1c on A549 cells and 2o on HepG2 cells, respectively, and the IC50 value of compound 1c on A549 cells exhibited the single μm range. (Source: Chemical Biology and ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5643712 Mon, 19 Dec 2011 05:00:00 +0100 5643712 http://www.medworm.com/index.php?rid=5520215&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01306.x In this study we have analyzed the transport characteristics of EM‐2 and three of its analogues (Dmt‐Pro‐Phe‐Phe‐NH2, Tyr‐(1S,2R)Acpc‐Phe‐Phe‐NH2 and Tyr‐(1S,2R)Achc‐Phe‐Phe‐NH2) using an in vitro BBB model. The lipohilicity of the analogues, as assessed by their octanol/water partition coefficients, was higher than that of EM‐2. The flux of all four peptides from the apical (blood) side to the basolateral (brain) side was not saturable in the 10 nM to 1 mM concentration range, suggesting that a passive mechanism plays a major role in their transport. The permeability coefficient of the analogues was significantly higher than that of EM‐2, suggesting increased BBB penetration properties. We conclude that due to their good peptidase resistance and improved tran... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5520215 Mon, 19 Dec 2011 05:00:00 +0100 5520215 http://www.medworm.com/index.php?rid=5520214&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01307.x A series of novel 2‐(4‐(2,4‐dimethoxybenzoyl)phenoxy)‐1‐(4‐(3‐(piperidin‐4‐yl)propyl) piperidin‐1‐yl)ethanone derivatives 9(a‐e) and 10(a‐g) were synthesized and characterized by 1H NMR, IR, mass spectral and elemental analysis. These novel compounds were evaluated for their antileukemic activity against two human leukemic cell lines (K562 and CEM) by using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazoliumbromide (MTT) assay. Some of the tested compounds showed good antiproliferative activity with IC50 values ranging from 1.6 μM to 8.0 μM. Compound 9c, 9e and 10f with an electron withdrawing halogen substituent at the para position on the phenyl ring showed excellent in vitro potency against tested human leukemia cells (K562 and CEM).© 2011 J... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5520214 Mon, 19 Dec 2011 05:00:00 +0100 5520214 http://www.medworm.com/index.php?rid=5520213&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01308.x AbstractPyrazolines, the well‐known five‐membered nitrogen‐containing heterocyclic compounds, have received considerable interests in the fields of medicinal and agricultural chemistry due to their broad spectrum of biological activities. To discover more potent antifungal compounds, a series of structurally related 1,3,5‐trisubstituted‐2‐pyrazoline derivatives have been synthesized by introducing furan rings regarded as bioactive substructure into the scaffold of pyrazolines and tested for their activities against six plant pathogenic fungi in vitro. The preliminary bioassays indicated that almost all synthesized compounds had displayed variable growth inhibitory effects on the tested pathogenic fungi. In particular, compounds 4, 7, 9, 12, 18, 19 and 38 displayed excellent ant... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5520213 Mon, 19 Dec 2011 05:00:00 +0100 5520213 http://www.medworm.com/index.php?rid=5520212&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01309.x AbstractLinear and non‐linear quantitative structure activity relationship (QSAR) models for predicting the inhibitory activities of sulfonamides toward different carbonic anhydrase (CA) isozymes were developed based on Multilinear regression (MLR), principal component ‐ artificial neural network (PC‐ANN) and correlation ranking ‐ principal component analysis (CR‐PCR) to identify a set of structurally based numerical descriptors. MLR was used to build linear QSAR models using 53 compounds with their quantum chemical descriptors. For each type of isozyme, a separate QSAR models were obtained. It was found that the hydration energy plays a significant role in the binding of ligands to the CAI isozyme whereas the presence of five‐membered ring was detected as a major factor for th... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5520212 Mon, 19 Dec 2011 05:00:00 +0100 5520212 http://www.medworm.com/index.php?rid=5520211&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01310.x AbstractLindolefia stylosa (Kar. and Kir.) is an important medicinal plant in central and west Asia. Seventeen compounds 1 (ethyl lithospermate), 2 (methyl lithospermate), 3 (lithospermate B), 4 (rosmarinic acid), 5 (methyl rosmarinate), 6 (ethyl rosmarinate), 7 (3‐O‐feruloyl‐6′‐O‐coumaroyl sucrose), 8 (3‐O‐feruloyl‐6′‐O‐caffeoyl sucrose), 9 (3,6′‐O‐diferuloyl sucrose), 10 (3,6′‐O‐diferuloyl‐1‐kestose), 11 (3‐O‐feruloyl‐6′‐O‐coumaroyl‐1‐kestose), 12 (3,6′‐O‐diferuloyl nystose), 13 (3‐O‐Feruloyl‐6′‐O‐coumaroyl nystose), 14 (p‐coumaric acid), 15 (ferulic acid), 16 (naphthalene glycoside (8‐O‐β‐D‐ glucopyranoside)) and, 17 (4′‐hydroxy‐5‐methoxy‐6,7‐methylenedioxyisoflavone), have been isolated fro... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5520211 Mon, 19 Dec 2011 05:00:00 +0100 5520211 http://www.medworm.com/index.php?rid=5520210&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01311.x A series of dehydroepiandrosterone derivatives containing an acid ester were synthesized and evaluated for their antitumor activity on ES‐2, A549 and HepG2 cells by the MTT assay. Most compounds showed antitumor activity while compounds 1c, 2i and 2o exhibited more potential inhibitory effects compared with dehydroepiandrosterone on ES‐2 cells, A549 cells and HepG2 cells, respectively© 2011 John Wiley & Sons A/S (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5520210 Mon, 19 Dec 2011 05:00:00 +0100 5520210 http://www.medworm.com/index.php?rid=5643714&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01301.x Insect β‐N‐acetyl‐D‐hexosaminidase, a chitin degrading enzyme, is physiologically important during the unique life cycle of the insect. OfHex1, a β‐N‐acetyl‐D‐hexosaminidase from the insect, Ostrinia furna, which was obtained by our laboratory (Gen Bank No.: ABI81756.1), was studied by molecular modeling as well as by molecular docking with its inhibitor, allosamidin. 3D model of OfHex1 was built through the ligand‐supported homology modeling approach. The binding modes of its substrate and inhibitor were proposed through docking and cluster analysis. The pocket’s size and shape of OfHex1 differ from that of human β‐N‐acetyl‐D‐hexosaminidase, which determined that allosamidin can selectively inhibit OfHex1 instead of human β‐N‐acetyl‐D‐hexosaminidase... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5643714 Fri, 16 Dec 2011 05:00:00 +0100 5643714 http://www.medworm.com/index.php?rid=5512204&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01299.x AbstractNeuraminidase (NA) is a major glycoprotein of influenza virus which is essential for viral infection. It offers a potential target for antiviral drug development. In order to develop potent NA inhibitors, pharmacophore models were generated by GALAHAD. 3D‐QSAR studies were carried out on 49 molecules. Both CoMFA (q2 = 0.720 and r2 = 0.947) and CoMSIA (q2 = 0.644 and r2 = 0.885) yielded reasonable results. A preliminary pharmacokinetic profile of these NAIs was predicted using Volsurf module.© 2011 John Wiley & Sons A/S (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5512204 Fri, 16 Dec 2011 05:00:00 +0100 5512204 http://www.medworm.com/index.php?rid=5512203&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01300.x AbstractDisruption of glycosylphosphatidylinositol (GPI) biosynthesis is genetically and chemically validated as a drug target against the protozoan parasite Trypanosoma brucei, the causative agent of African sleeping sickness. The N‐acetylglucosamine‐phosphatidylinositol de‐N‐acetylase (deNAc) is a zinc metalloenzyme responsible for the second step of GPI biosynthesis. We recently reported the synthesis of eight deoxy‐2‐C‐branched monosaccharides containing carboxylic acid, hydroxamic acid or N‐hydroxyurea substituents at the C2 position that may act as zinc binding groups. Here, we describe the synthesis of a glucocyclitol‐phospholipid incorporating a hydroxamic acid moiety, and report the biochemical evaluation of the monosaccharides and the glucocyclitol‐phospholipi... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5512203 Fri, 16 Dec 2011 05:00:00 +0100 5512203 http://www.medworm.com/index.php?rid=5512202&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01301.x AbstractInsect β‐N‐acetylhexosaminidase, a chitin degrading enzyme, is physiologically important during the unique life cycle of the insect. OfHex1, a β‐N‐acetylhexosaminidase from the insect, Ostrinia furna, which was obtained by our lab (Gen Bank No.: ABI81756.1), was studied by molecular modeling as well as molecular docking with its inhibitor, allosamidin. 3D model of OfHex1 was built through the ligand‐supported homology modeling approach. The binding modes of its substrate and inhibitor were proposed through docking and cluster analysis. The pocket’s size and shape of Ofhex1 differ from that of human β‐N‐acetylhexosaminidase, which determined that allosamidin can selectively inhibit Ofhex1 instead of human β‐N‐acetylhexosaminidase. Moreover, the multi‐target... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5512202 Fri, 16 Dec 2011 05:00:00 +0100 5512202 http://www.medworm.com/index.php?rid=5512201&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01302.x AbstractA group of novel N‐1 substituted indazole‐3‐carboxamide derivatives were synthesized and evaluated as inhibitors of poly(ADP‐ribose)polymerase‐1 (PARP‐1). A structure‐based design strategy was applied to a weakly active unsubstituted 1H‐indazole‐3‐carboxamide 2, by introducing a three carbon linker between 1H‐indazole‐3‐carboxamide and different heterocycles, and led to compounds 4 [1‐(3‐(piperidin‐1‐yl)propyl)‐1H‐indazole‐3‐carboxamide, IC50 = 36 μM] and 5 [1‐(3‐(2,3‐dioxoindolin‐1‐yl)propyl)‐1H‐indazole‐3‐carboxamide, IC50 = 6.8 μM]. Compound 5 was evaluated in rats for its protective action against diabetes induced by a treatment with streptozotocin (STZ), a known diabetogenic agent. In addition to preserving the abil... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5512201 Fri, 16 Dec 2011 05:00:00 +0100 5512201 http://www.medworm.com/index.php?rid=5512200&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01303.x AbstractN‐Protected cysteines 4a‐c each with a free sulfhydryl group were prepared in 70‐75% yields by treatment of L‐cysteine with 1‐(benzyloxycarbonyl)benzotriazole (Cbz‐Bt) 1a, N‐(tert‐butyloxy‐carbonyl)benzotriazole (Boc‐Bt) 1b and 1‐(9‐fluorenylmethoxy‐carbonyl)benzotriazole (Fmoc‐Bt) 1c, respectively. N‐Protected free sulfhydryl cysteines 4a‐c were then converted into the corresponding N‐protected free sulfhydryl cysteinoylbenzotriazoles 7a‐c (70‐85%), which on treatment with diverse amino acids and dipeptides afforded the corresponding N‐protected free sulfhydryl N‐terminal cysteine dipeptides 8a‐e and tripeptides 8f‐h in 73‐80% yields. N‐Protected free sulfhydryl cysteine containing dipeptides 9a,b were converted into the correspond... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5512200 Fri, 16 Dec 2011 05:00:00 +0100 5512200 http://www.medworm.com/index.php?rid=5512199&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01304.x A series of 3,5‐disubstituted‐1,2,4‐oxadiazoles has been prepared and evaluated for phosphodiesterase inhibition (PDE4B2). Among the prepared 3,5‐disubstituted‐1,2,4‐oxadiazoles, compound 9a is the most potent inhibitor (PDE4B2 IC50 = 5.28 μM). Structure‐activity relationship studies of 3,5‐disubstituted‐1,2,4‐oxadiazoles revealed that substituents 3‐cyclopentyloxy‐4‐methoxyphenyl group at 3‐position and cyclic ring bearing heteroatoms at 5‐position are important for activity. Molecular modeling study of the 3,5‐disubstituted‐1,2,4‐oxadiazoles with PDE4B has shown similar interactions of 3‐cyclopentyloxy‐4‐methoxyphenyl group, however, heteroatom ring is slightly deviating when compared to Piclamilast. 3‐(3‐Cyclopentyloxy‐4‐methoxyphenyl)�... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5512199 Fri, 16 Dec 2011 05:00:00 +0100 5512199 http://www.medworm.com/index.php?rid=5512208&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01293.x AbstractTraditional drug design is a laborious and expensive process that often challenges the pharmaceutical industries. As a result, researchers have turned to computational methods for computer‐assisted molecular design. Recently, genetic and evolutionary algorithms have emerged as efficient methods in solving combinatorial problems associated with computer‐aided molecular design. Further, combining genetic algorithms (GAs) with quantitative structure‐property relationship (QSPR) analyses has proved effective in drug design.In this work, we have integrated a new genetic algorithm and non‐linear QSPR models to develop a reliable virtual screening algorithm for generation of potential chemical penetration enhancers (CPEs). The GA‐QSPR algorithm has been implemented successfully ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5512208 Thu, 15 Dec 2011 05:00:00 +0100 5512208 http://www.medworm.com/index.php?rid=5512207&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01295.x AbstractDishevelled (Dvl) PDZ domains transduce Wnt signals from the membrane‐bound receptor Frizzled to the downstream. As abnormal Wnt signaling has been implicated in tumorigenesis, the Dvl PDZ domain is a potential target for small‐molecule inhibitors that block Wnt signaling at the Dvl level. We expanded our in silico search to examine the chemical space near previously developed PDZ binders and identified nine additional compounds bind to the Dvl PDZ. We then performed a quantitative structure‐activity relationship (QSAR) analysis of these compounds and combined these results with structural studies of the PDZ domain in complex with the compounds to design and synthesize a group of new, further optimized compounds. Two rounds of synthesis and testing yielded a total of six comp... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5512207 Thu, 15 Dec 2011 05:00:00 +0100 5512207 http://www.medworm.com/index.php?rid=5512206&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01296.x AbstractGenistein modulates inflammatory responses in part by reducing the production of the pro‐inflammatory cytokines IL‐12, TNF‐α and nitric oxide (NO), by activated macrophages in response to lipopolysaccharide (LPS) stimulus. Previous studies have shown that synthetic lipophilic genistein glycosides were significantly more active than hydrophilic glycosides. The aim of this study was to synthesize and evaluate the effect of novel lipophilic genistein derivatives on IL‐12, TNF‐α and NO production by J774A.1 cells. The results show that the modification of genistein enables the generation of non‐cytotoxic compounds with increased IL‐12 inhibition. However, these derivatives failed to inhibit TNF‐α. The NO production was notably inhibited by the monoester (2, 3) and mo... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5512206 Thu, 15 Dec 2011 05:00:00 +0100 5512206 http://www.medworm.com/index.php?rid=5512205&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01297.x AbstractResearch in chemical biology focuses on the use of small molecules to study protein functions and distinguish between different targets and their functional properties. In this context, it would be helpful to better understand which currently available active compounds have a potential to differentiate between different targets belonging to a protein family. Such compounds might be utilized as a starting point for the development of small molecular probes that distinguish one or more targets from others within a family of interest. In order to address this question, we have designed a computational approach for data mining that involves the generation and quantitative assessment of selectivity profiles for compounds active against a protein family. Selectivity profiles were generat... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5512205 Thu, 15 Dec 2011 05:00:00 +0100 5512205 http://www.medworm.com/index.php?rid=5592828&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01290.x Current treatment strategy for advanced prostate cancer is to suppress androgen receptor (AR) by castration and antiandrogens. However, several clinically relevant AR mutations cause insensitivity to current antiandrogens and convert them into agonists. We aim to identify full AR antagonists even for AR mutants. As crystal structure of AR ligand‐binding domain (LBD) at antagonistic form is not available, we decided to learn from estrogen receptor (ER) antagonism: (i) We built a structural model of wild‐type AR‐LBD complexed with antiandrogen bicalutamide (wild type/bicalutamide) using ERα‐LBD/hydroxytamoxifen structure as the template for helix‐12. (ii) By comparative structural analysis of 24 ERα‐LBD complexes, we found residues D351 and L354 at helix‐3 adopt unique confor... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5592828 Thu, 08 Dec 2011 05:00:00 +0100 5592828 http://www.medworm.com/index.php?rid=5492458&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01288.x Schistosomiasis, a high volume neglected tropical disease affecting more than 200 million people worldwide, can only be effectively treated by the tetrahydroisoquinoline drug praziquantel (PZQ). Herein, we describe an efficient approach to access PZQ derivatives by the Ugi 4‐component reaction followed by the Pictet‐Spengler reaction in a two‐step, one‐pot procedure. 30 Novel PZQ derivatives are described based on the Ugi 4‐component reaction and an X‐ray structure of a novel derivative revealing different conformation compared with PZQ is discussed. Several analogues comparable in activity to the drug PZQ have been identified based on an in vitro Schistosoma mansoni worm viability assay. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5492458 Thu, 08 Dec 2011 05:00:00 +0100 5492458 http://www.medworm.com/index.php?rid=5492457&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01290.x AbstractCurrent treatment strategy for advanced prostate cancer is to suppress androgen receptor (AR) by castration and antiandrogens. However, several clinically‐relevant AR mutations cause insensitivity to current antiandrogens and convert them into agonists. We aim to identify full AR antagonists even for AR mutants. Since crystal structure of AR ligand‐binding domain (LBD) at antagonistic form is not available, we decided to learn from estrogen receptor (ER) antagonism: i) We built a structural model of wild‐type AR‐LBD complexed with antiandrogen bicalutamide (WT/bicalutamide) using ERα‐LBD/hydroxytamoxifen structure as the template for helix‐12; ii) By comparative structural analysis of 24 ERα‐LBD complexes, we found residues D351 and L354 at helix‐3 adopt unique co... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5492457 Thu, 08 Dec 2011 05:00:00 +0100 5492457 http://www.medworm.com/index.php?rid=5643715&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01286.x It is widely appreciated that the vascular endothelium is capable of modulating vascular smooth muscle tone suiting it well for its role as an important regulator of a number of diverse biological processes. Endothelial dysfunction is an early manifestation of atherothrombosis and a consequence of the established disease. Although several arginine derivatives alkylated at one of the guanidino nitrogen were found to inhibit vasorelaxation induced by acetylcholine, activity of the corresponding arginine esters is not reported. The present work was therefore designed to synthesize and evaluate series of novel arginine derivatives to obtain further insight into structure–activity relationship in this series of compounds. Present study involves assessment of activity of these novel compounds ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5643715 Wed, 07 Dec 2011 05:00:00 +0100 5643715 http://www.medworm.com/index.php?rid=5592829&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01285.x Two molecular scaffolds were designed using the CAVEAT molecular design package to inhibit the oligomerization of protective antigen (PA63), a key protein component of anthrax toxin. The inhibitors were designed to prevent heptamerization of PA63 by mimicking key residues of PA63 needed for the intermolecular interactions that stabilize the heptamer. Using the scaffolds identified by CAVEAT, seven candidate inhibitors were synthesized and tested for their ability to inhibit anthrax toxin–induced cytotoxicity, with three of the agents demonstrating modest inhibition in murine J774A.1 macrophage cells.Structure‐based design methods were used to identify structures that mimic the key protein–protein interactions of the protective antigen (PA63) heptameric prepore of anthrax toxin. Seven... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5592829 Wed, 07 Dec 2011 05:00:00 +0100 5592829 http://www.medworm.com/index.php?rid=5482911&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01285.x AbstractTwo molecular scaffolds were designed using the CAVEAT molecular design package to inhibit the oligomerization of protective antigen (PA63), a key protein component of anthrax toxin. The inhibitors were designed to prevent heptamerization of PA63 by mimicking key residues of PA63 needed for the intermolecular interactions that stabilize the heptamer. Using the scaffolds identified by CAVEAT, seven candidate inhibitors were synthesized and tested for their ability to inhibit anthrax toxin‐induced cytotoxicity, with three of the agents demonstrating modest inhibition in murine J774A.1 macrophage cells. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5482911 Wed, 07 Dec 2011 05:00:00 +0100 5482911 http://www.medworm.com/index.php?rid=5482910&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01286.x AbstractIt is widely appreciated that the vascular endothelium is capable of modulating vascular smooth muscle tone suiting it well for its role as an important regulator of a number of diverse biological processes. Endothelial dysfunction is an early manifestation of atherothrombosis and a consequence of the established disease. Although several arginine derivatives alkylated at one of the guanidino nitrogen were found to inhibit vasorelaxation induced by acetylcholine, activity of the corresponding arginine esters is not reported. The present work was therefore designed to synthesize and evaluate series of novel arginine derivatives to obtain further insight into structure‐activity relationship in this series of compounds. Present study involves assessment of activity of these novel co... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5482910 Wed, 07 Dec 2011 05:00:00 +0100 5482910 http://www.medworm.com/index.php?rid=5643716&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01284.x The apoptosis‐inducing activity data of a series of 4‐aryl‐4H‐chromenes based on three cell lines (human breast cancer cell line T47D, human non‐smal cell lung cancer cell line H1299, and human colorectal cancer cell line DLD‐1) have been subjected to quantitative structure–activity relationship (QSAR) analysis. A collection of chemometrics methods including multiple linear regression (MLR), factor analysis–based multiple linear regression (FA‐MLR), principal component regression (PCR), and partial least squared combined with genetic algorithm for variable selection (GA‐PLS) were employed to make connections between structural parameters and induction of apoptosis in three different cell lines. Models of high statistical qualities were obtained for each cell line using ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5643716 Sat, 03 Dec 2011 05:00:00 +0100 5643716 http://www.medworm.com/index.php?rid=5473482&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01284.x Abstract  The apoptosis inducing activity data of a series of 4‐aryl‐4‐H‐chromenes based on three cell lines (human breast cancer cell line T47D, human nonsmal cell lung cancer cell line H1299, and human colorectal cancer cell line DLD‐1) have been subjected to quantitative structure‐activity relationship (QSAR) analysis. A collection of chemometrics methods including multiple linear regression (MLR), factor analysis‐based multiple linear regression (FA‐MLR), principal component regression (PCR) and partial least squared combined with genetic algorithm for variable selection (GA‐PLS) were employed to make connections between structural parameters and induction of apoptosis in three different cell lines. Models of high statistical qualities were obtained for each cell li... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5473482 Sat, 03 Dec 2011 05:00:00 +0100 5473482 http://www.medworm.com/index.php?rid=5473486&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01279.x AbstractCORAL (CORrelations And Logic, http://www.insilico.eu/coral/) is a freeware available on the Internet. This freeware is designed to build up quantitative structure – property/activity relationships (QSPRs/QSARs). The molecular structure for CORAL should be represented by the simplified molecular input line entry system (SMILES). Optimal descriptors calculated with SMILES are a mathematical function of the presence or absence of SMILES elements. The essence of this approach is the calculation of correlation weights for each element or combination of the elements by the Monte Carlo method. These coefficients serve to calculate the descriptor correlated with the endpoint for the training set, hoping that this correlation will also hold for the external test set. These descriptors ca... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5473486 Fri, 02 Dec 2011 05:00:00 +0100 5473486 http://www.medworm.com/index.php?rid=5473485&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01280.x AbstractThe deoxyglucose dithiocarbamate (DGDTC) was radiolabelled with 99mTc(V)‐glucoheptonate (GH), for the potential use as radiopharmaceuticals for tumor imaging. For labelling, 99mTcO‐DGDTC was prepared by ligand‐exchange reaction with 99mTc‐GH. The radiochemical purity (RCP) of the 99mTcO‐DGDTC complex was over 90% by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC), without any notable decomposition at room temperature over a period of 6 h. Its partition coefficient indicated that it was a hydrophilic complex. The ligand‐exchange reaction occured at neutral condition and under 100 °C for 15 min to achieve high RCP. In vitro cell studies showed there was an increase in the uptake of 99mTcO‐DGDTC as a function of incubation time and the ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5473485 Fri, 02 Dec 2011 05:00:00 +0100 5473485 http://www.medworm.com/index.php?rid=5473484&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01281.x AbstractIn addition to catalytic action, snake venom phospholipase A2 (PLA2) induces several pharmacological effects including neurotoxicity, cardiotoxicity as well as anti‐coagulant and anti‐platelet aggregation effects. Therefore, strategy to identify dual inhibitor for this enzyme will be of much importance in medical research. In this paper structure‐based pharmacophore mapping, molecular docking, protein ligand interaction fingerprints (PLIFs), binding energy calculations and binding affinity predictions were employed in a virtual screening strategy to identify new hits for dual inhibition of anti‐coagulation and inflammation of PLA2. A structure‐based pharmacophore map was modeled which comprised of important interactions as observed in co‐crystal of PLA2 and its dual inh... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5473484 Fri, 02 Dec 2011 05:00:00 +0100 5473484 http://www.medworm.com/index.php?rid=5473483&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01282.x AbstractPeptide phage display, a powerful method for ligand identification, was used to identify new peptide ligands for epidermal growth factor receptor (EGFR). A‐431 cells expressing EGFR were used as the matrix in a cell‐based subtractive biopanning approach using a seven‐mer peptide displaying phage library. Two novel peptide ligands were identified and tested for their affinities and functional effects on EGFR. The identified peptides were able to inhibit the EGF‐induced phosphorylation of EGFR in a concentration‐dependent manner. The results of affinity binding experiments showed that the natural ligand, i.e., EGF, was able to inhibit competitively the binding of peptide‐bearing phage to EGFR expressing A‐431 cells. Molecular modeling studies were used to calculate the ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5473483 Fri, 02 Dec 2011 05:00:00 +0100 5473483 http://www.medworm.com/index.php?rid=5512198&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01305.x AbstractA series of (1‐adamantyl)phthalimides, 1‐4, and (2‐adamantyl)phthalimides, 5‐8, characterized by different chain length between the adamantyl and the phthalimide moiety were synthesized, as well as 1‐ and 2‐adamantylphthalimides substituted by nitro 9, 10, and amino group 11, 12, and phthalimides bearing homoadamantyl 13 and protoadamantyl substituent 14 and 15. The compounds were tested for antiproliferative activity in vitro on a series of five human cancer lines: MCF‐7 (breast carcinoma), SW 620 (colon carcinoma), HCT 116 (colon carcinoma), MOLT‐4 (acute lymphoblastic leukemia), H 460 (lung carcinoma) and a non‐tumor cell line HaCaT (human keratinocytes). All compounds except nitro derivatives 9 and 10 exhibited antiproliferative activity. The activity was gene... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5512198 Thu, 01 Dec 2011 05:00:00 +0100 5512198 http://www.medworm.com/index.php?rid=5500980&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01291.x AbstractGlycogen synthase kinase‐3 (GSK‐3), a serine/threonine kinase, is a fascinating enzyme with diverse biological actions in intracellular signaling systems, making it an emerging target for diseases such as diabetes mellitus, cancer, chronic inflammation, bipolar disorders and Alzheimer’s disease. It is important to inhibit GSK‐3 selectively and the net effect of the GSK‐3 inhibitors thus should be target specific, over other phylogenetically related kinases such as CDK‐2. In the present work, we have carried out three‐dimensional quantitative structure activity relationship (3D‐QSAR) studies on novel class of 3‐anilino‐4‐aryl maleimide derivatives to have improved cellular activity. Docked conformation of the most active molecule in the series, which shows desi... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5500980 Thu, 01 Dec 2011 05:00:00 +0100 5500980 http://www.medworm.com/index.php?rid=5492456&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01289.x AbstractIn the present study antimycobacterial activity of a set of synthesized chalcone derivatives against Mycobacterium tuberculosis H37Rv were investigated by quantitative structure‐activity relationship (QSAR) analysis using density functional theory (DFT) and molecular mechanics (MM+) based descriptors in both gas and solvent phases. The best molecular descriptors identified were hardness, EHOMO, MRA‐4 and MRB‐4′ that contributed to the antimycobacterial activity of the chalcones as independent factors. The correlation of these four descriptors with their antimycobacterial activity increases with the inclusion of solvent medium indicating their importance in studying biological activity. QSAR models revealed that in gas phase, lower values of EHOMO, MRA‐4 and MRB‐4′ inc... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5492456 Thu, 01 Dec 2011 05:00:00 +0100 5492456 http://www.medworm.com/index.php?rid=5482909&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01287.x Very recently it has been shown that it is possible to selectively kill breast cancer stem cells using the ionophore antibiotic, salinomycin. Its ability to kill cancer stem cells and apoptosis‐resistant cancer cells may define salinomycin as a novel anticancer drug. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5482909 Thu, 01 Dec 2011 05:00:00 +0100 5482909 http://www.medworm.com/index.php?rid=5473481&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01283.x AbstractGalectin‐1 and galectin‐3 have roles in cancer and inflammation. Galectin‐1 has recently emerged as a significant protein produced by tumour cells to promote tumour development, angiogenesis and metastasis and consequently represents an important target to inhibit. The design of inhibitors targeting the carbohydrate recognition domain that is known to recognise galactose is an important approach in the fight against cancer. Based on analysis of crystal structures, we pursued the concept that if the galactose were to be replaced with talose (the C2 epimer of galactose) as a scaffold, then O2 substituents would be directed closer to the protein surface and provide opportunity to design inhibitors that are more specific toward particular galectins. Our elucidation of X‐ray cry... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5473481 Thu, 01 Dec 2011 05:00:00 +0100 5473481 http://www.medworm.com/index.php?rid=5465062&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01278.x AbstractNovel aminoquinoline β‐aminoalcohol and oxazolidinone derivatives were designed, synthesized and evaluated for in vitro antiplasmodial activity against a chloroquine‐sensitive (3D7) and chloroquine‐resistant (K1) strains of Plasmodium falciparum. A few β‐aminoalcohol derivatives were more potent than chloroquine against chloroquine‐sensetive Plasmodiums. The potency of these derivatives decreased against chloroquine‐resistant species in all cases (higher resistance indices), suggesting a possible cross resistance between this group of compounds and chloroquine which could be due to their structural similarity. Although changing β‐aminoalcohols to their oxazolidinone counterparts decreased the potency in all the cases, the compounds were still active and the resista... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5465062 Thu, 01 Dec 2011 05:00:00 +0100 5465062 http://www.medworm.com/index.php?rid=5465064&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01276.x AbstractsPlasmepsin II (PlmII), an aspartic protease expressed in the food vacuole of Plasmodium falciparum (pf), cleaves the hemoglobin of the host during the erythrocytic stage of the parasite life cycle. Various peptidomimetic inhibitors of PlmII reported so far discriminate poorly between the drug target and aspartic proteases of the host organism, e.g. human cathepsin D (hCatD). hCatD is a protein‐digestion enzyme and signaling molecule involved in a variety of physiological processes, therefore, inhibition of hCatD by PlmII inhibitors may lead to patophysiological conditions. In this paper, binding of PlmII inhibitors have been modeled using the crystal structures of pfPlmII and hCatD complexes to gain insight into structural requirements underlying the target selectivity. A seri... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5465064 Wed, 30 Nov 2011 05:00:00 +0100 5465064 http://www.medworm.com/index.php?rid=5465063&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01277.x AbstractA recent discovery of aromatase crystal structure triggered the efforts to design novel aromatase inhibitors (AIs) for breast cancer therapy. While correlating docking scores with inhibitory potencies of known ligands, feeble robustness of scoring functions towards prediction was observed. This prompted us to develop new prediction models using stepwise regression analysis based on consensus of different docking and their scoring methods (GOLD, LigandFit and GLIDE). Quantitative structure activity relationships were developed between the aromatase inhibitory activity (pIC50) of flavonoidal derivatives (n=39) and docking scores and docking descriptors. QSAR models have been validated internally [using leave‐one‐out cross‐validated r2cv (LOO‐Q2)] and externally to ensure the ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5465063 Wed, 30 Nov 2011 05:00:00 +0100 5465063 http://www.medworm.com/index.php?rid=5447541&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01275.x In this study, taking into account both the L‐D and cis‐trans isomerisms, a comprehensive structural characterization and a comparative conformational analysis were performed on the thirty‐two stereoisomeric forms of opioid tetrapeptide, endomorphin‐2. For all stereoisomers, the Φ‐Ψ and χ conformational spaces were explored, in the course of which the conformational distributions, as well as the rotamer states of aromatic side‐chains were characterized in detail. Furthermore, the typical β‐ and γ‐turn structures, as well as the characteristic intramolecular interactions (i.e. H‐bonds, aromatic‐aromatic and proline‐aromatic interplays) were determined. The afore‐mentioned structural and conformational features identified for each stereoisomeric form were compare... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5447541 Sat, 26 Nov 2011 08:38:35 +0100 5447541 http://www.medworm.com/index.php?rid=5447542&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01274.x The T box antiterminator RNA element is an important component of the T box riboswitch that controls the transcription of vital genes in many Gram‐positive bacteria. A series of 1,4‐disubstituted 1,2,3‐triazoles was screened in a fluorescence‐monitored thermal denaturation assay to identify ligands that altered the stability of antiterminator model RNA. Several ligands were identified that significantly increased or decreased the melting temperature (Tm) of the RNA. The results indicate that this series of triazole ligands can alter the stability of antiterminator model RNA in a structure‐dependent manner. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5447542 Fri, 25 Nov 2011 05:00:00 +0100 5447542 http://www.medworm.com/index.php?rid=5437153&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01271.x Abstract3,5‐bis(2‐fluorobenzylidine)‐4‐piperidone or EF24 is a potent anticancer derivative of curcumin. Using an amine derivative of EF24, we synthesized a hydrazinonicotinic acid conjugate, EFAH, for Tc‐99m radiolabeling and SPECT imaging. The aqueous solubility of EFAH (3.5 mg/ml) was significantly more than that of EF24 (1.2 mg/ml); the octanol/water partition coefficient of EFAH was estimated at log P = 0.33. As an antiproliferative agent, EFAH was as effective as EF24 in suppressing the proliferation of H441, MiaPaCa‐2 and Panc‐1 cells. Daily intraperitoneal injection of EFAH (5 μg) for 3 weeks in mice carrying xenografts of Panc‐1 pancreatic cancer showed a mean tumor volume reduction of 79%; the tumor weight decreased by 82% in the treated group. For imaging and bi... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5437153 Wed, 23 Nov 2011 07:39:57 +0100 5437153 http://www.medworm.com/index.php?rid=5437154&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01270.x We report herein bicyclic hydroxy‐1H‐pyrrolopyridine‐triones as a new family of HIV‐1 integrase inhibitors that were efficiently prepared using a key “Pummerer cyclization deprotonation cycloaddition” cascade of imidosulfoxides. In in vitro HIV‐1 integrase assays the analogues showed low micromolar inhibitory potencies with selectively for strand transfer reactions as compared with 3’‐processing inhibition. A representative inhibitor (5e) retained most of its inhibitory potency against the three major raltegravir‐resistance mutant IN enzymes, G140S/Q148H, Y143R and N155H. In antiviral assays employing viral vectors coding these IN mutants, compound 5e was approximately 200‐fold and 20‐fold less affected than raltegravir against the G140S/Q148H and Y143R mutations, r... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5437154 Tue, 22 Nov 2011 05:00:00 +0100 5437154 http://www.medworm.com/index.php?rid=5417346&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01206.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5417346 Thu, 17 Nov 2011 22:22:45 +0100 5417346 http://www.medworm.com/index.php?rid=5417345&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01260.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5417345 Thu, 17 Nov 2011 22:22:44 +0100 5417345 http://www.medworm.com/index.php?rid=5404664&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01269.x AbstractIn this work 17 new N‐acylhydrazone derivatives of amino acids have been evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv. The compounds 8b, 8e, 8f, 9a‐d and 10c were non‐cytotoxic and exhibited an important minimum inhibitory concentration (MIC) activity between 12.5 and 50 μg/mL, which can be compared with that of the tuberculostatic drug D‐cycloserine (20 μg/mL). (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5404664 Tue, 01 Nov 2011 04:00:00 +0100 5404664 http://www.medworm.com/index.php?rid=5396622&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01268.x AbstractOn the basis of evidence that opioid compounds with a mixed μ agonist/δ antagonist profile may produce an antinociceptive effect with low propensity to induce side effects, bifunctional opioid peptides containing the μ agonist [Dmt1]DALDA (H‐Dmt‐D‐Arg‐Phe‐Lys‐NH2; Dmt = 2’,6’‐dimethyltyrosine) connected tail‐to‐tail via various α,ω‐diaminoalkyl‐ or diaminocyclohexane linkers to the δ antagonists TICP[Ψ] (H‐Tyr‐TicΨ[CH2‐NH]Cha‐Phe‐OH; Cha = cyclohexylalanine, Tic = 1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid), H‐Dmt‐Tic‐OH or H‐Bcp‐Tic‐OH (Bcp = 4’‐[N‐((4’‐phenyl)phenethyl)carboxamido]phenylalanine) were synthesized and pharmacologically characterized in vitro. Bifunctional [Dmt1]DALDA→NH‐(CH2)n‐NH←... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5396622 Tue, 01 Nov 2011 04:00:00 +0100 5396622 http://www.medworm.com/index.php?rid=5374960&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01267.x The aspartate biosynthetic pathway provides essential metabolites for many important biological functions, including the production of four essential amino acids. Since this critical pathway is only present in plants and microbes any disruptions will be fatal to these organisms. An early pathway enzyme, L‐aspartate‐β‐semialdehyde dehydrogenase (ASADH), produces a key intermediate at the first branch point of this pathway. Developing potent and selective inhibitors against several orthologs in the ASADH family can serve as lead compounds for antibiotic development. Kinetic studies of two small molecule fragment libraries have identified inhibitors that show good selectivity against ASADHs from two different bacterial species, Streptococcus pneumoniae and Vibrio cholerae, despite the ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5374960 Tue, 01 Nov 2011 04:00:00 +0100 5374960 http://www.medworm.com/index.php?rid=5374971&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01239.x Activating gene rearrangements of anaplastic lymphoma kinase (ALK) have been identified as driver mutations in non‐small‐cell lung cancer, inflammatory myofibroblastic tumors, and other cancers. Crizotinib, a dual MET/ALK inhibitor, has demonstrated promising clinical activity in patients with non‐small‐cell lung cancer and inflammatory myofibroblastic tumors harboring ALK translocations. Inhibitors of driver kinases often elicit kinase domain mutations that confer resistance, and such mutations have been successfully predicted using in vitro mutagenesis screens. Here, this approach was used to discover an extensive set of ALK mutations that can confer resistance to crizotinib. Mutations at 16 residues were identified, structurally clustered into five regions around the kinase acti... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5374971 Mon, 31 Oct 2011 04:00:00 +0100 5374971 http://www.medworm.com/index.php?rid=5355199&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01266.x AbstractA series of novel pyrazole and triazole derivatives containing 5‐phenyl‐2‐furan functionality were designed and synthesized. Their toxicities were predicted in silico assays and proven to be less toxic. The antitumor results showed that the activity of compounds containing 1,3,4‐triazole (series II) was higher than that of pyrazole‐attached derivatives (series I). Among them, IIa and IIg showed much higher activity against Bel‐7402 than Doxorubicin. The fungicidal tests showed that most title compounds II exhibited great selectivity against Phytophthora capsici in vivo. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5355199 Fri, 28 Oct 2011 00:24:08 +0100 5355199 http://www.medworm.com/index.php?rid=5355200&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01265.x AbstractOxovanadium (IV) complexes of N, N′‐bispyridoxyl‐5, 5′‐bis (phosphate) ethylenediimine (L1) and N,N′‐bis(pyridoxyl)‐5,5′‐bis(phosphate)‐1′′‐(p‐nitrobenzyl)ethylenediimine (L2) were synthesized by condensation of optically active C‐substituted diamines and pyridoxal‐5‐phosphate (P‐5‐P). Oxovanadium (IV) complexes derived from L1 and L2 were evaluated as DNA cleavage agent (cleavage of supercoiled plasmid pBR322 DNA). Interestingly, both the oxovanadium(IV) complexes exhibited DNA nuclease activity and the extent of oxidation of DNA by these vanadyl complexes was superior to VOSO4. The significant reduction in primary tumor and increased delay in tumor growth of 15 days was seen in the tumor regression analysis with Oxovanadium(IV) complex of L... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5355200 Mon, 24 Oct 2011 04:00:00 +0100 5355200 http://www.medworm.com/index.php?rid=5343417&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01264.x AbstractFour highly discriminating fourth generation topological indices (TIs), termed as superaugmented eccentric distance sum connectivity indices as well as their topochemical versions (denoted by,,and ) have been conceptualized in the present study. The values of these indices for all possible structures with three, four and five vertices containing one heteroatom were computed using an in‐house computer program. The proposed superaugmented eccentric distance sum connectivity topochemical indices exhibited exceptionally high discriminating power, low degeneracy and high sensitivity towards both the presence and the relative position of heteroatom (s) for all possible structures with five vertices containing at least one heteroatom. Intercorrelation analysis revealed the absence of co... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5343417 Sun, 23 Oct 2011 23:23:44 +0100 5343417 http://www.medworm.com/index.php?rid=5453949&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01262.x Current treatment of leishmaniasis is based on chemotherapy, which relies on a handful of drugs with serious limitations, such as high cost, toxicity, and lack of efficacy in endemic regions. Therefore, development of new, effective, and affordable anti‐leishmanial drugs is a global health priority. Dipeptidylcarboxypeptidase has been characterized and established as a drug target for antileishmanial drug discovery. We virtually screened a large chemical library of 15 452 compounds against a 3D model of dipeptidylcarboxypeptidase to identify novel inhibitors. The initial virtual screening using a ligand‐based pharmacophore model identified 103 compounds. Forty‐six compounds were shortlisted based on the docking scores and other scoring functions. Further, these compounds were subje... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5453949 Thu, 20 Oct 2011 04:00:00 +0100 5453949 http://www.medworm.com/index.php?rid=5343420&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01261.x The development of highly selective small molecule inhibitors for individual caspases, a class of cysteine‐dependent aspartate‐specific proteases, has been challenging due to conservation of the active site. Previously we discovered an allosteric site at the dimer interface of caspases‐3, ‐7 and ‐1 using disulfide trapping. Here we show this approach can generate selective tethered ligands and inhibitors for caspase‐5 which is remarkable considering its high sequence similarity to caspase‐1. Among the 62 hit out of a screen of ∼15,000 thiol‐containing fragments, a naphthyl‐thiazole containing molecule was identified that selectively inhibited and labeled the allosteric cysteine in the p10 subunit of caspase‐5, but caused very little inhibition or labeling of caspase�... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5343420 Thu, 20 Oct 2011 04:00:00 +0100 5343420 http://www.medworm.com/index.php?rid=5343419&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01262.x AbstractCurrent treatment of leishmaniasis is based on chemotherapy, which relies on a handful of drugs with serious limitations such as high cost, toxicity and lack of efficacy in endemic regions. Therefore, development of new, effective and affordable anti‐leishmanial drugs is a global health priority. Dipeptidylcarboxypeptidase has been characterized and established as a drug target for antileishmanial drug discovery. We virtually screened a large chemical library of 15,452 compounds against a 3D model of dipeptidylcarboxypeptidase to identify novel inhibitors. The initial virtual screening using a ligand‐based pharmacophore model identified 103 compounds. Forty‐six compounds were short listed based on the docking scores and other scoring functions. Further, these compounds were s... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5343419 Thu, 20 Oct 2011 04:00:00 +0100 5343419 http://www.medworm.com/index.php?rid=5343418&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01263.x A series of norephedrine‐based Schiff bases (1a‐6a and 1b‐6b) were synthesized by reacting substituted salicylaldehydes with d‐norephedrine or l‐norephedrine. The structure of these compounds was confirmed by elemental analyses and spectroscopic techniques. The molecular structures of 5a and 6a have been determined by X‐ray crystallography, which revealed that the compounds are in the oxoamino form, with bent intramolecular N‐H···O (N···O ≈ 2.58 Å) hydrogen bonds and that they are associated in dimers bridged by linear intermolecular O‐H···O (O···O ≈ 2.69 Å) hydrogen bonds. DFT calculations on 5a confirmed that the oxoamino form is more stable than the phenolimino form by 12.2 kcal/mol. All the compounds were evaluated for their antibacterial activity usin... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5343418 Thu, 20 Oct 2011 04:00:00 +0100 5343418 http://www.medworm.com/index.php?rid=5321407&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01247.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5321407 Sun, 16 Oct 2011 10:17:40 +0100 5321407 http://www.medworm.com/index.php?rid=5321405&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01259.x We report the synthesis and fibrillogenesis inhibiting activity of the new peptide derivatives 1‐4, related to the pentapeptide Ac‐LPFFD‐NH2 (iAβ5p), proposed by Soto and coworkers and widely recognized as one of the most active β‐sheet breaker agents. The Aβ25‐35 fragment of the parent full‐length Aβ1‐42 was used as fibrillogenesis model. The activity of peptide derivatives 1‐4 was tested in vitro by thioflavin T binding assay, far UV CD spectroscopy, and scanning electron microscopy. Their ability to hinder the toxic effect of Aβ25‐35in vivo was studied by monitoring the viability of human SH‐SY5Y neuroblastoma cells and the prevention of superoxide anion radical release from BV2 microglial cells. The results point to a favourable role in the fibrillogenesis inhi... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5321405 Sun, 16 Oct 2011 10:16:52 +0100 5321405 http://www.medworm.com/index.php?rid=5417344&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01259.x We report the synthesis and fibrillogenesis inhibiting activity of the new peptide derivatives 1–4, related to the pentapeptide Ac‐LPFFD‐NH2 (iAβ5p), proposed by Soto and co‐workers and widely recognized as one of the most active β‐sheet breaker agents. The Aβ25–35 fragment of the parent full‐length Aβ1–42 was used as fibrillogenesis model. The activity of peptide derivatives 1–4 was tested in vitro by thioflavin T binding assay, far UV CD spectroscopy, and scanning electron microscopy. Their ability to hinder the toxic effect of Aβ25–35in vivo was studied by monitoring the viability of human SH‐SY5Y neuroblastoma cells and the prevention of superoxide anion radical release from BV2 microglial cells. The results point to a favourable role in the fibrillogenesis i... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5417344 Thu, 13 Oct 2011 04:00:00 +0100 5417344 http://www.medworm.com/index.php?rid=5321406&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01258.x AbstractInhibiting PLA2 activity should, in theory, be an effective approach to control the inflammation. Several naturally occurring polyphenolic compounds have been reported as inhibitors of PLA2. Among the naturally occurring polyphenols catechol (1,2‐dihydroxybenzene) possesses anti‐inflammatory activity. Catechol can inhibit cyclooxygenase and lipoxygenase. By means of enzyme kinetic study it was revealed that catechol can inhibit PLA2 also. Crystal structure showed that catechol binds to PLA2 at the opening of the active site cleft. This might stop the entry of substrate into the active site. Hence catechol can be used as a lead compound for the development of novel anti‐inflammatory drugs with PLA2 as the target. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5321406 Thu, 13 Oct 2011 04:00:00 +0100 5321406 http://www.medworm.com/index.php?rid=5374966&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01257.x The biological activities of parthenolide, a sesquiterpene lactone isolated from feverfew, have been attributed to the presence of the α‐methylene‐γ‐lactone skeleton. The lactone skeleton can react via the Michael type addition with sulfhydryl groups of enzymes and other functional proteins, interfering with key biological processes in the cell. In the present study, we describe an efficient method of preparation of 3‐isopropyl‐2‐methyl‐4‐methyleneisoxazolidin‐5‐one (MZ‐6), a synthetic compound with α‐methylene‐γ‐lactone ring, as in parthenolide, additionally modified by introduction of a nitrogen atom. Furthermore, we investigated the cytotoxic activity and anti‐metastatic potential of MZ‐6 in comparison with parthenolide. Both compounds showed consider... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5374966 Wed, 12 Oct 2011 04:00:00 +0100 5374966 http://www.medworm.com/index.php?rid=5427871&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01255.x A series of quinoline‐incorporated substituted thiadiazole were designed and synthesized using appropriate synthetic route keeping in view the structural requirement of pharmacophore and evaluated for anticonvulsant and CNS activities. After intraperitoneal injection to mice, some synthesized derivatives were examined in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazol (scPTZ)‐induced seizure and neurotoxicity screens. Those found potent were also evaluated for behavioural impairment and depression activity. Among the compounds tested, 6d and 6e showed protection from seizures in both the animal models at dose level of 30 mg/kg while 7f showed protection against both models at 100 mg/kg dose level. These compounds exhibited lesser CNS depression and neuroto... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5427871 Mon, 10 Oct 2011 04:00:00 +0100 5427871 http://www.medworm.com/index.php?rid=5310587&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01255.x AbstractA series of quinoline incorporated substituted thiadiazole were designed & synthesized using appropriate synthetic route keeping in view the structural requirement of pharmacophore and evaluated for anticonvulsant and CNS activities. After intraperitoneal injection to mice, some synthesized derivatives were examined in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazol (scPTZ) induced seizure and neurotoxicity screens. Those found potent were also evaluated for behavioural impairment and depression activity. Among the compounds tested, 6d & 6e, showed protection from seizures in both the animal models at dose level of 30 mg/kg while 7f showed protection against both models at 100 mg/kg dose level. These compounds exhibited lesser CNS depression and ne... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5310587 Mon, 10 Oct 2011 04:00:00 +0100 5310587 http://www.medworm.com/index.php?rid=5310586&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01256.x AbstractActivity cliffs are formed by structurally similar compounds with significant differences in potency and represent an extreme form of SAR discontinuity. By contrast, regions of SAR continuity in compound data sets result from the presence of structurally increasingly diverse compounds retaining similar activity. Previous studies have revealed that SAR information extracted from large compound data sets is often heterogeneous in nature containing both continuous and discontinuous SAR components. SAR discontinuity and continuity are often represented by different compound series, independent of each other. Here we have searched different compound data sets for the presence of SAR continuity within the vicinity of prominent activity cliffs. For this purpose, we have designed and imple... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5310586 Mon, 10 Oct 2011 04:00:00 +0100 5310586 http://www.medworm.com/index.php?rid=5374964&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01249.x The small molecule carrier class of biomolecule transporters, modeled on the third helix of the Antennapedia homeodomain, has previously been shown to transport active proteins into cells. Here, we show an improved synthetic route to small molecule carriers, including Molander chemistry using trifluoroborate salts to improve the yield of the Suzuki–Miyaura coupling step for the formation of the biphenyl backbone. The required boronic acids could be formed by the reaction of a 2‐(dimethylamino)ethyl ether‐modified aryl Grignard reagent with triisopropyl borate. The potential for the use of small molecule carriers as oligonucleotide‐transporting agents was also explored by characterizing the interactions between small molecule carriers and siRNA. Molecular dynamics and NMR analysis i... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5374964 Sat, 08 Oct 2011 04:00:00 +0100 5374964 http://www.medworm.com/index.php?rid=5447543&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01252.x Defining the role of calcitonin gene‐related peptide in migraine pathogenesis could lead to the application of calcitonin gene‐related peptide antagonists as novel migraine therapeutics. In this work, quantitative structure–activity relationship modeling of biological activities of a large range of calcitonin gene‐related peptide antagonists was performed using a panel of physicochemical descriptors. The computational studies evaluated different variable selection techniques and demonstrated shuffling stepwise multiple linear regression to be superior over genetic algorithm‐multiple linear regression. The linear quantitative structure–activity relationship model revealed better statistical parameters of cross‐validation in comparison with the non‐linear support vector regre... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5447543 Tue, 04 Oct 2011 04:00:00 +0100 5447543 http://www.medworm.com/index.php?rid=5374967&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01251.x This study determined the in vitro potential of novel compounds adamantyl‐N‐acetylcystein and adamantyl isothiocyanate to treat gynecological cancers. Adamantyl‐N‐acetylcystein is postulated to be an in vivo metabolite of adamantyl isothiocyanate as dietary isothiocyanates are converted to N‐acetylcysteine‐conjugates. A viability assay suggested that adamantyl isothiocyanate and adamantyl‐N‐acetylcystein are cytotoxic to cancer cells including gynecological cell lines. A NCI60 cancer cell assay revealed that growth‐inhibition and cytotoxicity of adamantyl‐N‐acetylcystein were cell line, but not tissue type‐specific. Cell cycle studies revealed that adamantyl‐N‐acetylcystein and adamantyl isothiocyanate arrest SKOV‐3 ovarian cancer cells in G2/M phase. By TUNEL... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5374967 Tue, 04 Oct 2011 04:00:00 +0100 5374967 http://www.medworm.com/index.php?rid=5292711&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01251.x AbstractThe present study determined the in vitro potential of novel compounds adamantyl‐N‐acetylcystein (AC‐AM) and adamantyl‐Isothiocyanate (ITC‐AM) to treat gynecological cancers. AC‐AM is postulated to be an in vivo metabolite of ITC‐AM since dietary isothiocyanates are converted to N‐acetylcysteine‐conjugates. A viability assay suggested that ITC‐AM and AC‐AM are cytotoxic to cancer cells including gynecological cell lines. A NCI60 cancer cell assay revealed that growth‐inhibition and cytotoxicity of AC‐AM were cell line‐ but not tissue type‐specific. Cell cycle studies revealed that AC‐AM and ITC‐AM arrest SKOV‐3 ovarian cancer cells in G2/M phase. By TUNEL‐, immunoblotting‐ and viability‐studies employing caspase and p38 MAPK inhibitors we p... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5292711 Tue, 04 Oct 2011 04:00:00 +0100 5292711 http://www.medworm.com/index.php?rid=5281290&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01250.x MEK‐1 and MEK‐2 are dual specificity kinases and important components in the MAPK pathway. These enzymes are crucial for normal cell survival and are also expressed in several types of cancers making them important targets for drug design. We have applied an integrated in‐silico approach that combines CoMFA, CoMSIA and molecular docking, to study the structural determinants for recognition of substituted isothiazole analogs as allosteric inhibitors against MEK‐1 kinase. The best 3D‐QSAR models for CoMFA and CoMSIA were selected based on statistical parameters. 3D contour maps suggested that bulky or long chain substitutions at the X‐ position on the core part decreases the inhibitory activity and the presence of a hydrogen bond donor substitution enhances the activity. The bulk... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5281290 Mon, 03 Oct 2011 04:00:00 +0100 5281290 http://www.medworm.com/index.php?rid=5310585&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01257.x AbstractThe biological activities of parthenolide, a sesquiterpene lactone isolated from feverfew, have been attributed to the presence of the α‐methylene‐γ‐lactone skeleton. The lactone skeleton can react via the Michael type addition with sulfhydryl groups of enzymes and other functional proteins, interfering with key biological processes in the cell. In the present study we describe an efficient method of preparation of 3‐isopropyl‐2‐methyl‐4‐methyleneisoxazolidin‐5‐one (MZ‐6), a synthetic compound with α‐methylene‐γ‐lactone ring, as in parthenolide, additionally modified by introduction of a nitrogen atom. Furthermore, we investigated the cytotoxic activity and anti‐metastatic potential of MZ‐6 in comparison with parthenolide. Both compounds showed c... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5310585 Sat, 01 Oct 2011 04:00:00 +0100 5310585 http://www.medworm.com/index.php?rid=5301683&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01249.x AbstractThe Small Molecule Carrier (SMoC) class of biomolecule transporters, modelled on the third helix of the Antennapedia homeodomain, has previously been shown to transport active proteins into cells. Here, we show an improved synthetic route to SMoCs, including Molander chemistry using trifluoroborate salts to improve the yield of the Suzuki‐Miyaura coupling step for formation of the biphenyl backbone. The required boronic acids could be formed by reaction of a 2‐(dimethylamino)ethyl ether‐modified aryl Grignard reagent with triisopropyl borate. The potential for the use of SMoCs as oligonucleotide transporting agents was also explored by characterising the interactions between SMoCs and siRNA. Molecular dynamics and NMR analysis indicated that the SMoC guanidines are stabilised... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5301683 Sat, 01 Oct 2011 04:00:00 +0100 5301683 http://www.medworm.com/index.php?rid=5292710&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01252.x AbstractDefining the role of calcitonin gene‐related peptide (CGRP) in migraine pathogenesis could lead to the application of CGRP antagonists as novel migraine therapeutics. In the present work, quantitative structure activity relationship (QSAR) modeling of biological activities of a large range of CGRP antagonists was performed using a panel of physicochemical descriptors. The computational studies evaluated different variable selection techniques and demonstrated shuffling stepwise multiple linear regression (MLR) to be superior over genetic algorithm‐MLR. The linear QSAR model revealed better statistical parameters of cross validation in comparison with the nonlinear support vector regression technique. Implementing only five peptide descriptors into this linear QSAR model resulte... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5292710 Sat, 01 Oct 2011 04:00:00 +0100 5292710 http://www.medworm.com/index.php?rid=5281289&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01248.x In this study, we report the screening of 9 compounds of flavonoids from the ZINC and PubChem databases (containing 2,092 flavonoids) using the iGEMDOCK software tool against the XO and COX‐2 3D protein structures. Each compound was also evaluated by an in vitro bioassay testing the inhibition of XO and COX‐2. Myricetin and luteolin were found to be the potential dual inhibitors of XO and COX‐2 as demonstrated by IC50: 62.7 and 3.29μg/mL (XO) / 70.8 and 16.38μg/mL (COX‐2), respectively. In addition, structure activity relationships and other important factors of the flavonoids binding to the active site of XO and COX‐2 were discussed, which is expected for further rational drug design. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5281289 Sat, 01 Oct 2011 04:00:00 +0100 5281289 http://www.medworm.com/index.php?rid=5268460&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01232.x A series of novel naphthalimide derivatives with 4‐[4‐(3,3‐diphenylallyl)piperazin‐1‐yl]benzoic acid as side chain were designed and synthesized. Their antitumor activities were evaluated against a variety of cancer cell lines in vitro. Preliminary results showed that most of the derivatives had cytotoxic activity comparable with that of amonafide, with IC50 values of 10−6–10−5 m. Interestingly, compound 12e had the unique antitumor activity against MCF‐7 among the cancer cell lines tested. More importantly, flow cytometric analysis indicated that compared with amonafide, the target compounds could effectively induce G2/M arrest and progress to apoptosis in HL‐60 cells after double staining with annexin V–FITC and propidium iodide. The present work provided a novel ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5268460 Thu, 29 Sep 2011 04:00:00 +0100 5268460 http://www.medworm.com/index.php?rid=5257145&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01246.x AbstractTwenty new quinoxalines bearing azetidinone and thiazolidinone groups were synthesized by cyclocondensation of Schiff bases of quinoxaline‐2, 3‐Dione and were characterised with several analytical tools. They were tested against Mycobacterium tuberculosis H37Rv at a concentration of 10μg/ml by Microplate Alamar Blue Assay method. Quinoxaline derivatives with 2‐chloro, dimethylamino and nitro substitutions exhibited in vitro activity, comparable to that of the drug, isoniazid. 3D‐QSAR studies indicated that electrostatic and steric field descriptors could explain the observed activity. The developed model fits the data well and has good predictive capability (r2 = 0.81, q2 = 0.71, F = 27.06, pred_ r2 = 0.84, rm2 = 0.84, r2 BS = 0.80). Electronegative groups play an importan... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5257145 Tue, 27 Sep 2011 00:37:29 +0100 5257145 http://www.medworm.com/index.php?rid=5246083&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01244.x AbstractEleven new amino alcohol derivatives have been synthesized from reactions of lopinavir intermediate and heteroaromatic aldehyde in good yields. These compounds, the antiretrovirals (lopinavir and ritonavir) and lopinavir key intermediate were evaluated as antibacterial agents against Mycobacterium tuberculosis H37Rv using the Alamar Blue susceptibility test and their activity expressed as the minimum inhibitory concentration (MIC) in μM. Ten amino alcohols evaluated displayed significant activity (MIC between 6.15 and 108.4 μM) when compared to first line drug ethambutol (MIC = 15.9). Three of them showed more activity than ethambutol (MIC = 6.15; 6.21 and 13.4). The appreciable activity of these compounds can be considered an important finding for the rational design of new lead... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5246083 Fri, 23 Sep 2011 08:26:48 +0100 5246083 http://www.medworm.com/index.php?rid=5374968&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01245.x Tubulin inhibition represents an established target in the field of anticancer research, and over the last 20 years, an intensive search for new antimicrotubule agents has occurred. Indeed, in silico models have been presented that might aid the discovery of novel agents. Among these, a 7‐point pharmacophore model has been recently proposed. As a formal proof of this model, we carried out a ligand‐based virtual screening on the colchicine‐binding site. In vitro testing demonstrated that two compounds displayed a cytotoxic profile on neuroblastoma cancer cells (SH‐SY5H) and one had an antitubulinic profile.An intensive search for new antimicrotubule agents has occurred. Indeed, in silico models have been presented that might aid the discovery of novel agents. Among these, a 7‐po... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5374968 Fri, 23 Sep 2011 04:00:00 +0100 5374968 http://www.medworm.com/index.php?rid=5257146&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01245.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5257146 Fri, 23 Sep 2011 04:00:00 +0100 5257146 http://www.medworm.com/index.php?rid=5233188&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01243.x AbstractBased on the N‐(phenethyl)azole backbone of azole antifungals, we designed 1‐[(2‐benzyloxy)phenyl]‐2‐(azol‐1‐yl)ethanone derivatives 2 and 3, containing benzyloxyphenyl scaffold of croconazole. Also these compounds can be considered as flexible analogs, resulted from C2–C3 disconnection of 3′‐chloro‐3‐imidazolylflavanone 1, recently described as antifungal agent. Thus, in this report, we describe the synthesis of 1‐[(2‐benzyloxy)phenyl]‐2‐(azol‐1‐yl)ethanone derivatives 2 and 3, and their biological evaluation against different pathogenic fungi. By comparing the antifungal activity profile of flexible compounds 2 and 3 with that of rigid analog 1, it can be inferred that lower susceptibilities (higher MICs) were observed with flexible compounds. ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5233188 Mon, 19 Sep 2011 22:02:18 +0100 5233188 http://www.medworm.com/index.php?rid=5374969&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01240.x The Keap1–Nrf2 interaction plays important roles in regulation of Nrf2 activity and induction of chemopreventive enzymes. To better understand the interaction and to determine the minimal Nrf2 sequence required for Keap1 binding, we synthesized a series of Nrf2 peptides containing ETGE motif and determined their binding affinities to the Kelch domain of Keap1 in solution using a surface plasmon resonance‐based competition assay. The equilibrium dissociation constant for the interaction between 16mer Nrf2 peptide and Keap1 Kelch domain in solution () was found to be 23.9 nm, which is 10× lower than the surface binding constant () of 252 nm obtained for the direct binding of Keap1 Kelch domain to the immobilized 16mer Nrf2 peptide on a surface plasmon resonance sensor chip surface. ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5374969 Thu, 15 Sep 2011 04:00:00 +0100 5374969 http://www.medworm.com/index.php?rid=5355203&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01241.x A series of 3‐thiazolidine acetic acid‐2‐(per‐O‐acetylglycosyl)‐1′‐imino‐α‐(substituted)‐4‐oxo ethyl ester derivatives (3a–t) were prepared via the reaction of substituted amino acid‐N‐[(per‐O‐acetylglycosylamino)thioxomethyl]‐ethyl ester with ethyl bromoacetate. The crystal structure of 3‐thiazolidine acetic acid‐2‐(2′,3′,4′,6′‐tetra‐O‐acetyl‐β‐d‐galactoyranosyl)‐1′‐imino‐α‐methyl‐4‐oxo ethyl ester 3g and 1H‐13C HMBC (2D NMR experiments) measurements of 3‐thiazolidine acetic acid‐2‐(2′,3′,4′,6′‐tetra‐O‐acetyl‐β‐d‐galactopyranosyl)‐1′‐imino‐α‐(1‐methylthio)ethyl‐4‐oxo ethyl ester 3j revealed the exclusive regioselectivity during the closure of these rings toward the ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5355203 Thu, 15 Sep 2011 04:00:00 +0100 5355203 http://www.medworm.com/index.php?rid=5355202&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01242.x This study demonstrates the first reported analysis of pentacyclo[5.3.0.02,5.03,9.04,8]decane as a potential therapeutic agent.As part of an ongoing project to develop highly potent anti‐tuberculosis therapeutics, a series novel polycyclic ‘cage’ tetra‐amines were synthesized and screened for in‐vitro anti‐tuberculosis activities against the H37Rv strain of tuberculosis. Compounds 5 and 7 showed similar activity to SQ109 at a MIC of 1 μm while compounds 4, 6 and 8 displayed MIC activity at 1<MIC<10 μm against H37Rv strain of tuberculosis. Compounds 5 and 7 also showed excellent activity against MDR and XDR Tb strains. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5355202 Thu, 15 Sep 2011 04:00:00 +0100 5355202 http://www.medworm.com/index.php?rid=5233198&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01240.x AbstractThe Keap1‐Nrf2 interaction plays important roles in regulation of Nrf2 activity and induction of chemopreventive enzymes. To better understand the interaction and to determine the minimal Nrf2 sequence required for Keap1 binding, we synthesized a series of Nrf2 peptides containing ETGE motif and determined their binding affinities to the Kelch domain of Keap1 in solution using a surface plasmon resonance (SPR)‐based competition assay. The equilibrium dissociation constant for the interaction between 16mer Nrf2 peptide and Keap1 Kelch domain in solution (KDsolution) was found to be 23.9 nM, which is 10× lower than the surface binding constant (KDsurface) of 252 nM obtained for the direct binding of Keap1 Kelch domain to the immobilized 16mer Nrf2 peptide on a SPR sensor chip su... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5233198 Thu, 15 Sep 2011 04:00:00 +0100 5233198 http://www.medworm.com/index.php?rid=5233190&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01241.x A series of 3‐thiazolidine acetic acid‐2‐(per‐O‐acetylglycosyl)‐1′‐imino‐α‐(substituted)‐4‐oxo ethyl ester derivatives (3a‐t) were prepared via the reaction of substituted amino acid‐N‐[(per‐O‐acetylglycosylamino)thioxomethyl]‐ethyl ester with ethyl bromoacetate. The crystal structure of 3‐thiazolidine acetic acid‐2‐(2′, 3′, 4′, 6′‐tetra‐O‐acetyl‐β‐D‐galactoyranosyl)‐1′‐imino‐α‐methyl‐4‐oxo ethyl ester 3g and 1H‐13C HMBC measurements of 3‐thiazolidine acetic acid‐2‐(2′, 3′, 4′, 6′‐tetra‐O‐acetyl‐β‐D‐galactopyranosyl)‐1′‐imino‐α‐(1‐methylthio)ethyl‐4‐oxo ethyl ester 3j revealed the exclusive regioselectivity during the closure of these rings towards the N‐2 position... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5233190 Thu, 15 Sep 2011 04:00:00 +0100 5233190 http://www.medworm.com/index.php?rid=5233189&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01242.x This study demonstrates the first reported analysis of pentacyclo[5.3.0.02,5.03,9.04,8]decane as a potential therapeutic agent. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5233189 Thu, 15 Sep 2011 04:00:00 +0100 5233189 http://www.medworm.com/index.php?rid=5355204&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01238.x Human placental alkaline phosphatase has been identified as a hydrolase that is significantly overexpressed on the surface of various solid tumor cells, and is therefore a suitable prodrug design target for non‐invasive cancer imaging and therapy. Structure‐based prediction of enzymatic activities is essential for rational prodrug design. We have been probing the catalytic proficiency – (kcat/KM)/kw– of placental alkaline phosphatase toward several widely diverse substrate structures experimentally and correlating these results to in silico predictions that are based on the free energy estimates obtained from docking of each substrate structure with placental alkaline phosphatase. We have found that electrostatic contribution from the tail group is the most crucial factor to determ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5355204 Mon, 12 Sep 2011 04:00:00 +0100 5355204 http://www.medworm.com/index.php?rid=5233200&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01238.x AbstractHuman placental alkaline phosphatase (PLAP) has been identified as a hydrolase that is significantly overexpressed on the surface of various solid tumor cells, thereby a suitable prodrug design targets for non‐invasive cancer imaging and therapy. Structure‐based prediction of enzymatic activities is essential for rational prodrug design. We have been probing the catalytic proficiency – (kcat/KM)/kw– of PLAP towards several widely‐diverse substrate structures experimentally and correlating these results to in silico predictions that are based on the free energy estimates obtained from docking of each substrate structure with PLAP. We have found that electrostatic contribution from the tail group is the most crucial factor to determine the catalytic efficiencies of the subs... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5233200 Mon, 12 Sep 2011 04:00:00 +0100 5233200 http://www.medworm.com/index.php?rid=5203966&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01194.x Here, we describe the practical synthesis and biological properties of bergenin and its structural analogs. Synthetic bergenin compounds were prepared by acylation of bergenin. These compounds were then evaluated for suppression of lipopolysaccharide‐induced nitric oxide (NO) generation in cultured cells and anti‐narcotic effects on morphine‐dependent mice. We found that bergenin derivatives showed potent anti‐inflammatory activity (suppression of NO generation) at concentrations ranging from 20 to 30 μmin vitro, and bergenin derivatives (10–20 mg/kg) exhibited significant anti‐narcotic effects on morphine dependence in mice. These results suggest the potential utility of bergenin and its analogs as anti‐narcotic agents and the design of more potent anti‐inflammatory c... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5203966 Sun, 11 Sep 2011 03:34:44 +0100 5203966 http://www.medworm.com/index.php?rid=5203965&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01181.x In this study, the antitubercular properties of purine and 2,3‐dihydropurine derivatives have been investigated. A quantitative structure‐activity relationship model, able to predict whether new purine and 2,3‐dihydropurine derivatives belong to an ‘Active’ or ‘Inactive’ class against Mycobacterium tuberculosis, was developed. Such prediction model, which is based on a classification tree and involves a small number of descriptors, allowed us to outline structural features important to predict antitubercular activity of such classes of compounds. (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5203965 Sun, 11 Sep 2011 03:34:43 +0100 5203965 http://www.medworm.com/index.php?rid=5203964&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01179.x Neuraminidase (NA) is a major glycoprotein of influenza virus which is essential for viral infection. It offers a potential target for antiviral drug design and discovery. To develop novel potent neuraminidase inhibitors (NAI), Surflex‐Dock was employed to dock 40 hydrophobic p‐aminosalicylic acid derivatives into the active site of NA. The 3D‐quantitative structure–activity relationship studies involving comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were carried out on 40 molecules. Both CoMFA (q2 = 0.628, r2 = 0.697) and CoMSIA (q2 = 0.746, r2 = 0.816) gave reasonable results. A preliminary pharmacokinetic profile of these NAI was also performed on the basis of Volsurf predictions. The results obtained ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5203964 Sun, 11 Sep 2011 03:34:41 +0100 5203964 http://www.medworm.com/index.php?rid=5203963&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01176.x Forty‐four novel chalcone‐inspired analogs having a 3‐aryl‐2‐propenoyl moiety derived from alicyclic ketones were designed, synthesized, and investigated for cytotoxicity against murine B16 and L1210 cancer cell lines. The analogs belong to four structurally divergent series, three of which (series g, h, and i) contain differently substituted cyclopentanone units and the fourth (series j) contains a 3,3‐dimethyl‐4‐piperidinone moiety. Of these, the analogs in series j showed potential cytotoxic activity against murine B16 (melanoma) and L1210 (lymphoma) cells. The most active compounds 5j, 11j, 15j, and 12h produced IC50 values from 4.4 to 15 μm against both cell lines. A single‐crystal X‐ray structure analysis and molecular modeling studies confirmed that these chal... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5203963 Sun, 11 Sep 2011 03:34:40 +0100 5203963 http://www.medworm.com/index.php?rid=5203962&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01202.x Microsomal prostaglandin E synthase‐1 (mPGES‐1) is the key enzyme for prostaglandin E2 (PGE2) generation during inflammation and is a potential target for designing anti‐inflammatory drugs. Potential inhibitors of m‐PGES‐1 were selected from traditional Chinese medicine (TCM Database@Taiwan) based on the pharmacophore map generated by the top HypoGen hypothesis and validated using structure‐ and ligand‐based analysis. Key features for potential m‐PGES‐1 inhibitors include pi‐interactions and H‐bond donors. TCM compounds, shanciol B, shanciol A, castilliferol, and aurantiamide acetate, contoured to the quantitative structure–activity relationship pharmacophore and exhibited high docking scores and binding stability with m‐PGES‐1. Bioactivity models multiple linea... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5203962 Sun, 11 Sep 2011 03:34:36 +0100 5203962 http://www.medworm.com/index.php?rid=5203961&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01197.x In this study, the effects of five new synthetic benzofuranone derivatives were investigated on the insulin amyloid formation process. Protein fibrillation was analyzed by thioflavin‐T fluorescence, Congo red binding, circular dichroism, and electron microscopy. Despite high structural similarity, one of the five tested compounds was observed to enhance amyloid fibrillation, while the others inhibited the process when used at micromolar concentrations, which could make them interesting potential lead compounds for the design of therapeutic antiamyloidogenic compounds.Amyloids are protein fibrils resulting from protein self‐assembly and contribute to pathological conditions known as amyloidoses. Insulin is prone to form amyloid fibrils under in vivo conditions when injected in diabetic ... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5203961 Sun, 11 Sep 2011 03:34:33 +0100 5203961 http://www.medworm.com/index.php?rid=5203960&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01189.x Noscapine, the benzylisoquinoline alkaloid, 5‐(4,5‐Dimethoxy‐3‐oxo‐1,3‐dihydro‐isobenzofuran‐1‐yl)‐4‐methoxy‐6‐methyl‐5,6,7,8‐tetrahydro‐[1,3]dioxolo[4,5‐g]isoquinolin‐6‐ium, has been extensively used as a cough‐suppressing medication with low toxicity. It has been recently shown to also have anti‐cancer activity in mice and humans. In this work, using in silico analyses, the most probable binding site for noscapine is identified to be at the intradimer region of the α and β subunits of the tubulin heterodimer. By utilization of small molecule docking techniques, and an analysis of the thermodynamically favorable binding modes of noscapine in its binding site, the key residues of tubulin monomers interacting with noscapine are determined. Upon no... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5203960 Sun, 11 Sep 2011 03:34:14 +0100 5203960 http://www.medworm.com/index.php?rid=5203959&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01217.x (Source: Chemical Biology and Drug Design) Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5203959 Sun, 11 Sep 2011 03:34:07 +0100 5203959 http://www.medworm.com/index.php?rid=5374970&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01236.x In the current study, boosting regression has been proposed to model the activities of a series of phosphoramidate prodrugs of 2′‐methylcytidine as inhibitors of hepatitis C virus. The stepwise multiple linear regression and particle swarm optimization strategies are used to select descriptors which are responsible for the inhibitory activity of these compounds. As comparisons to the boosting regression method, the multiple linear regression, back‐propagation neural networks, and support vector machine have also been investigated. Experimental results have shown that the boosting can drastically enhance the generalization performance of individual multiple linear regression model and the particle swarm optimization‐boosting method is a well‐performing technique in quantitative st... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5374970 Sat, 03 Sep 2011 04:00:00 +0100 5374970 http://www.medworm.com/index.php?rid=5355205&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01234.x Here, we describe the design and synthesis of two series of 4‐pyrrylamino quinazolines as new analogs of the epidermal growth factor receptor inhibitor gefitinib. In vitro antitumor activity of these novel compounds against pancreatic (Miapaca2) and prostate (DU145) cancer cell lines was evaluated. Compared with the parental gefitinib, all 18 derivatives show a greatly increased cytotoxicity to cancer cells. In vitro kinase inhibitory activity on epidermal growth factor receptor was also investigated. Among them, compounds GI‐6, GII‐4, GII‐6, GII‐8, and GII‐9 are more potential receptor tyrosine kinase (RTK) inhibitors. Based on these results, we propose simple structure–activity relationship to provide information for designing and developing more potent antitumor agents.Two... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5355205 Sat, 03 Sep 2011 04:00:00 +0100 5355205 http://www.medworm.com/index.php?rid=5355201&cid=s_32060_62_f&fid=32060&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1747-0285.2011.01237.x Hypoxic regions of tumours are associated with increased resistance to radiation and chemotherapy. Nevertheless, hypoxia has been used as a tool for specific activation of some antitumour prodrugs, named bioreductive agents. Phenazine dioxides are an example of such bioreductive prodrugs. Our 2D‐quantitative structure activity relationship studies established that phenazine dioxides electronic and lipophilic descriptors are related to survival fraction in oxia or in hypoxia. Additionally, statistically significant models, derived by partial least squares, were obtained between survival fraction in oxia and comparative molecular field analysis standard model (r2 = 0.755, q2 = 0.505 and F = 26.70) or comparative molecular similarity indices analysis‐combined steric and electr... Chemical Biology and Drug Design journals http://www.medworm.com/rss/comments.php?id=5355201 Sat, 03 Sep 2011 04:00:00 +0100 5355201