Chemical Biology and Drug DesignThis is an RSS file. You can use it to subscribe to this data in your favourite RSS reader, such as GoogleReader, or to display this data on your own website or blog. Subscribe to this data using MyMedWorm.Subscribe to this data using GoogleReader.Subscribe to this data using Bloglines.Subscribe to this data using MyYahoo.

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Shape- and Chemical Feature-Based 3D-Pharmacophore Model Generation and Virtual Screening: Identification of Potential Leads for P. falciparum DHFR Enzyme InhibitionEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Plasmodium falciparum dihydrofolate reductase (Pf DHFR) enzyme is one of the validated targets in the treatment of malaria using typical antifolates such as cycloguanil and pyrimethamine. However, point mutations at amino acid residues such as Ala16, Ile51, Cys59, Ser108 and Ile164 in the active site of the wild-type enzyme resulted in a widespread resistance of the parasite to these drugs. Thus, design and discovery of new potential Pf DHFR inhibitors, equally active against both the wild-type and mutant strains, is an urgent need. Catalyst software was used to generate a 3D pharmacophore query based on the bioactive conf...
Source: Chemical Biology and Drug Design - November 6, 2009 Category: Biology Authors: Legesse Adane, Dhilon. S. Patel, Prasad V. Bharatam Source Type: journals

Structural Analysis of DFG-in and DFG-out Dual Src-Abl Inhibitors Sharing a Common Vinyl Purine TemplateEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Bcr-Abl is the oncogenic protein tyrosine kinase responsible for chronic myeloid leukemia (CML). Treatment of the disease with imatinib (Gleevec) often results in drug resistance via kinase mutations at the advanced phases of the disease, which has necessitated the development of new mutation-resistant inhibitors, notably against the T315I gatekeeper mutation. As part of our efforts to discover such mutation resistant Abl inhibitors, we have focused on optimizing purine template kinase inhibitors, leading to the discovery of potent DFG-in and DFG-out series of Abl inhibitors that are also potent Src inhibitors. Here we pre...
Source: Chemical Biology and Drug Design - November 5, 2009 Category: Biology Authors: Tianjun Zhou, Lois Commodore, Wei-Sheng Huang, Yihan Wang, Tomi K. Sawyer, William C. Shakespeare, Tim Clackson, Xiaotian Zhu, David C. Dalgarno Source Type: journals

Synthesis and Pharmacological Evaluation of Analogs of Indole-Based Cannabimimetic AgentsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Aminoalkylindoles (AAIs), although structurally dissimilar from the classical cannabinoids, are known to be capable of binding to cannabinoid receptors and of evoking cannabinomimetic responses. With the aim of investigating the structure[ndash]activity relationships (SAR) for the binding of non-classical agonists to CB1 and CB2 cannabinoid receptors, we designed and synthesized a series of indole derivatives. The compounds were tested for their analgesic action by formalin test and compared to WIN 55212-2, an AAI acting to the cannabinoid receptors. In receptor binding assay, compound 5 showed affinity for the CB1 recepto...
Source: Chemical Biology and Drug Design - November 5, 2009 Category: Biology Authors: Orazio Mazzoni, Maria V. Diurno, Antonio M. di Bosco, Ettore Novellino, Paolo Grieco, Giovanni Esposito, Alessia Bertamino, Antonio Calignano, Roberto Russo Source Type: journals

The X-Ray Structure of Carboxypeptidase A Inhibited by a Thiirane Mechanism-Based InhibitorEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The three-dimensional X-ray crystal structure of carboxypeptidase A, a zinc-dependent hydrolase, covalently modified by a mechanism-based thiirane inactivator, 2-benzyl-3,4-epithiobutanoic acid, has been solved to 1.38 Å resolution. The interaction of the thiirane moiety of the inhibitor with the active site zinc ion promotes its covalent modification of Glu-270 with the attendant opening of the thiirane ring. The crystal structure determination at high resolution allowed for the clear visualization of the covalent ester bond to the glutamate side chain. The newly generated thiol from the inhibitor binds to the catalytic ...
Source: Chemical Biology and Drug Design - November 4, 2009 Category: Biology Authors: Daniel Fernández, Sebastian Testero, Josep Vendrell, Francesc X. Avilés, Shahriar Mobashery Source Type: journals

Design and Characterization of an Acid-Activated Antimicrobial PeptideEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we developed a prototype antimicrobial peptide capable of achieving high activity exclusively at low environmental pH to target bacterial species like Streptococcus mutans that produce acid and thrive under the low pH conditions detrimental for tooth integrity. The features of clavanin A, a naturally occurring peptide rich in histidine and phenylalanine residues with pH-dependent antimicrobial activity, served as a design basis for these prototype 'acid-activated peptides' (AAPs). Employing the major cariogenic species S. mutans as a model system, the two AAPs characterized in this study exhibited a striking...
Source: Chemical Biology and Drug Design - October 29, 2009 Category: Biology Authors: Lina Li, Jian He, Randal Eckert, Daniel Yarbrough, Renate Lux, Maxwell Anderson, Wenyuan Shi Source Type: journals

Structure-based Drug Metabolism Predictions for Drug DesignEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we review important progress in drug metabolism and common in silico techniques adopted to predict drug regioselectivity, stereoselectivity, reactive metabolites, induction, inhibition and mechanism-based inactivation, as well as their implementation in hit-to-lead drug discovery. (Source: Chemical Biology and Drug Design)
Source: Chemical Biology and Drug Design - October 28, 2009 Category: Biology Authors: Hao Sun, Dennis O. Scott Source Type: journals

Resveratrol is Not a Direct Activator of SIRT1 Enzyme ActivityEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Resveratrol is a plant polyphenol capable of exerting beneficial metabolic effects which are thought to be mediated in large by the activation of the NAD+-dependent protein deacetylase SIRT1. Although resveratrol has been claimed to be a bona fide SIRT1 activator using a peptide substrate (Fluor de Lys-SIRT1 peptide substrate), recent reports indicate that this finding might be an experimental artifact and need to be clarified. Here, we show that: (i) the Fluor de Lys-SIRT1 peptide is an artificial SIRT1 substrate because in the absence of the covalently linked fluorophore the peptide itself is not a substrate of the enzym...
Source: Chemical Biology and Drug Design - October 20, 2009 Category: Biology Authors: Dirk Beher, John Wu, Suzanne Cumine, Ki Won Kim, Shu-Chen Lu, Larissa Atangan, Minghan Wang Source Type: journals

The Design, Synthesis and Potential Utility of Fluorescence Probes that Target DFG-out Conformation of p38α for High Throughput Screening Binding AssayEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The design, synthesis and utility of fluorescence probes that bind to the DFG-out conformation of p38[alpha] kinase are described. Probes that demonstrate good affinity for p38[alpha], have been identified and one of the probes, PF-04438255, has been successfully used in an high throughput screening (HTS) assay to identify two novel non-classical p38[alpha] inhibitors. In addition, a cascade activity assay was utilized to validate the selective binding of these non-classical kinase inhibitors to the unactive form of the enzyme. (Source: Chemical Biology and Drug Design)
Source: Chemical Biology and Drug Design - October 19, 2009 Category: Biology Authors: Haile Tecle, Frederic Feru, Hu Liu, Cyrille Kuhn, Glen Rennie, Mark Morris, Jiangxing Shao, Alan C. Cheng, Diana Gikunju, Juan Miret, Rocco Coli, Simon (Hualin) Xi, Susan L. Clugston, Simon Low, Steven Kazmirski, Yuan-Hua Ding, Qing Cao, Theresa L. Johnso Source Type: journals

Chemical Biology & Drug Design 2009: Transition, Scholarship and FaithEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Chemical Biology and Drug Design)
Source: Chemical Biology and Drug Design - October 19, 2009 Category: Biology Authors: Tomi K. Sawyer Source Type: journals

Combined 3D-QSAR Modeling and Molecular Docking Study on Quinoline Derivatives as Inhibitors of P-selectinEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
P-selectin is a promising target for developing novel atherosclerosis drugs. To understand the structure[ndash]activity correlation of quinolines-based P-selectin inhibitors, we have carried out a combined molecular docking and three-dimensional quantitative structure[ndash]activity relationship (3D-QSAR) modeling study. The study has resulted in two types of satisfactory 3D-QSAR models, including the CoMFA model (r2, 0.863; q2, 0.589) and CoMSIA model (r2, 0.866; q2, 0.636), to predict the biological activity of new compounds. The detailed microscopic structures of P-selectin binding with inhibitors have been studied by m...
Source: Chemical Biology and Drug Design - October 19, 2009 Category: Biology Authors: Huahui Zeng, Ran Cao, Huabei Zhang Source Type: journals

QM/MM Study of Epitope Peptides Binding to HLA-A*0201: The Roles of Anchor Residues and WaterEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
A hybrid quantum mechanics/molecular mechanics scheme is described to explore the structural basis and energetic behavior of short peptide segments binding to HLA-A*0201. This method was used to analyze 50 structurally diverse non-americ peptides and results showed that the quantum mechanics/molecular mechanics-derived interaction energy, in conjugation with empirical desolvation free energy, linearly correlate well with the experimentally determined affinity. Further systematic investigations of several HLA-A*0201[ndash]peptide complexes confirmed the importance of anchor residues and water molecules in peptide binding, a...
Source: Chemical Biology and Drug Design - October 19, 2009 Category: Biology Authors: Yuanchao Li, Yadong Yang, Ping He, Qingwu Yang Source Type: journals

Calendar of Events – December 2009Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Chemical Biology and Drug Design)
Source: Chemical Biology and Drug Design - October 15, 2009 Category: Biology Source Type: journals

Ligand-based 3D-QSAR Studies of Physostigmine Analogues as Acetylcholinesterase InhibitorsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This study will facilitate the rational design of more potent Physostigmine compounds which might have better activity and reduce toxicity for the treatment of Alzheimer disease. (Source: Chemical Biology and Drug Design)
Source: Chemical Biology and Drug Design - October 14, 2009 Category: Biology Authors: Zaheer Ul-Haq, Uzma Mahmood, Bushra Jehangir Source Type: journals

Activity Prediction and Structural Insights of Extracellular Signal-Regulated Kinase 2 Inhibitors with Molecular Dynamics SimulationsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
A computational application to predict, probe and interpret the activities of a series of congeneric compounds inhibiting extracellular signal-regulated kinase 2 protein kinase is presented. The study shows that molecular dynamics coupled with molecular mechanics Poisson[ndash]Boltzmann solvent accessible surface area free energy estimation is a suitable tool for investigating the experimental binding activities of ligands to protein kinases. Computed and experimental binding activities were found to be significantly correlated. Moreover, the interpretation of the X-ray co-crystal structure in conjunction with computationa...
Source: Chemical Biology and Drug Design - October 14, 2009 Category: Biology Authors: Alberto Del Rio, Benedetta Frida Baldi, Giulio Rastelli Source Type: journals

Carbonic Anhydrase Inhibitors: Glycosylsulfanilamides Act as Subnanomolar Inhibitors of the Human Secreted Isoform VIEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
A series of sulfonamides incorporating sugar moieties and the sulfanilamide scaffold have been investigated for their interaction with the secretory isoform of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), CA VI. This isoform is secreted in saliva, tears, and milk of mammals [ndash] where it plays important physiological roles [ndash] even if little is understood at this moment regarding its inhibition, due to the lack of potent and/or selective inhibitors. Here we report a series of low nanomolar and subnanomolar CA VI inhibitors, belonging to the glycosylamine[ndash]sulfanilamide class. The glucose, ribose, arabin...
Source: Chemical Biology and Drug Design - October 12, 2009 Category: Biology Authors: Jean-Yves Winum, Jean-Louis Montero, Daniela Vullo, Claudiu T. Supuran Source Type: journals

Rationalizing Protein–Ligand Interactions for PTP1B Inhibitors Using Computational MethodsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This study is an attempt to transform this data into useful knowledge which can be directly used to design more effective protein tyrosine phosphatase inhibitors. In this study, we have built quantitative models for activity of co-crystallized protein tyrosine phosphatase inhibitors using two new approaches developed in our group, i.e. receptor[ndash]ligand interaction and Structure-based compound optimization, prioritization and evolution based on receptor[ndash]ligand interaction descriptors and residue-wise interaction energies as descriptors, respectively. These models have given insights into the receptor[ndash]ligand...
Source: Chemical Biology and Drug Design - October 11, 2009 Category: Biology Authors: Subhash Ajmani, Sudheer Karanam, Sudhir A. Kulkarni Source Type: journals

Synthesis, Kinetic Characterization and Metabolism of Diastereomeric 2-(1-(4-Phenoxyphenylsulfonyl)ethyl)thiiranes as Potent Gelatinase and MT1-MMP InhibitorsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We describe herein the synthesis and evaluation of these structural variants as potent inhibitors of gelatinases. Two (compounds 5b and 5d) among the four synthetic stereoisomers were found to exhibit slow-binding inhibition of gelatinases and MMP-14 (MT1-MMP), which is a hallmark of the mechanism of this class of inhibitors. The ability of these compounds to inhibit MMP-2, MMP-9, and MMP-14 could target cancer tissues more effectively. Metabolism of the newly synthesized inhibitors showed that both oxidation at the [alpha]-position to the sulfonyl group and oxidation at the para position of the terminal phenyl ring were p...
Source: Chemical Biology and Drug Design - October 11, 2009 Category: Biology Authors: Major Gooyit, Mijoon Lee, Dusan Hesek, Bill Boggess, Allen G. Oliver, Rafael Fridman, Shahriar Mobashery, Mayland Chang Source Type: journals

The Anti-tumor Effects of Androstene Steroids Exhibit a Strict Structure–Activity Relationship Dependent upon the Orientation of the Hydroxyl Group on Carbon-17Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Androstene steroids are metabolites of dehydroepiandrosterone and exist as androstene-diols or -triols in [alpha]- and [beta]-epimeric forms based upon the placement of the hydroxyl groups relative to the plane of the [Delta]5cycloperhydrophenanthrene ring. 5-Androstene-3[beta],17[beta]-diol (3[beta],17[beta]-AED) functions to upregulate immunity and the addition of a third hydroxyl group at C-7 in the [alpha]- or [beta]-orientation (3[beta],7[alpha],17[beta]-AET and 3[beta],7[beta],17[beta]-AET, respectively) enhances the immunological activity of the molecule. In contrast, 5-androstene-3[beta],17[alpha]-diol (3[beta],17[...
Source: Chemical Biology and Drug Design - October 11, 2009 Category: Biology Authors: Martin R. Graf, Wentao Jia, Marvin L. Lewbart, Roger M. Loria Source Type: journals

Active Site Ring-Opening of a Thiirane Moiety and Picomolar Inhibition of GelatinasesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(±)-2-[(4-Phenoxyphenylsulfonyl)methyl]thiirane 1 is a potent and selective mechanism-based inhibitor of the gelatinase sub-class of the zinc-dependent matrix metalloproteinase family. Inhibitor 1 has excellent activity in in vivo models of gelatinase-dependent disease. We demonstrate that the mechanism of inhibition is a rate-limiting gelatinase-catalyzed thiolate generation via deprotonation adjacent to the thiirane, with concomitant thiirane opening. A corollary to this mechanism is the prediction that thiol-containing structures, related to thiirane-opened 1, will possess potent matrix metalloproteinase inhibitory act...
Source: Chemical Biology and Drug Design - October 6, 2009 Category: Biology Authors: Christopher Forbes, Qicun Shi, Jed F. Fisher, Mijoon Lee, Dusan Hesek, Leticia I. Llarrull, Marta Toth, Michael Gossing, Rafael Fridman, Shahriar Mobashery Source Type: journals

Cellular Fingerprints: A Novel Approach Using Large-Scale Cancer Cell Line Data for the Identification of Potential Anticancer AgentsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The cellular fingerprint, a novel in silico screening approach, was developed to identify new biologically active compounds in combination with structural fingerprints. To this end, high-throughput screening (HTS) data from the National Cancer Institute have been used. To validate this method, we have selected the proapoptotic, natural compound betulinic acid (BA). Because of its antiproliferative effect on a variety of cancer cell lines, the identification of novel BA analogs is of great interest. Novel analogs have been identified and validated in different apoptosis assays. In addition, the novel approach exhibited a st...
Source: Chemical Biology and Drug Design - October 2, 2009 Category: Biology Authors: Melanie Füllbeck, Mathias Dunkel, Julia Hossbach, Peter T. Daniel, Robert Preissner Source Type: journals

Three-Dimensional Protein–Ligand Interaction Scaling of Two-Dimensional FingerprintsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We introduce a computational scaling methodology that utilizes protein[ndash]ligand interaction information extracted from complex crystal structures to enrich similarity searching using structural fingerprints with compound class-specific information. Scaling factors are derived to emphasize fingerprint bit positions that result from interacting fragments of bound ligands and correspond to frequently occurring structural features. Through interaction-based scaling, this information is transferred to standard fingerprints of multiple reference compounds. In systematic search calculations, fingerprints scaled on the basis o...
Source: Chemical Biology and Drug Design - September 28, 2009 Category: Biology Authors: Lu Tan, Martin Vogt, Jürgen Bajorath Source Type: journals

A Thermodynamic Approach to the Affinity Optimization of Drug CandidatesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
High throughput screening and other techniques commonly used to identify lead candidates for drug development usually yield compounds with binding affinities to their intended targets in the mid-micromolar range. The affinity of these molecules needs to be improved by several orders of magnitude before they become viable drug candidates. Traditionally, this task has been accomplished by establishing structure activity relationships to guide chemical modifications and improve the binding affinity of the compounds. As the binding affinity is a function of two quantities, the binding enthalpy and the binding entropy, it is ev...
Source: Chemical Biology and Drug Design - September 27, 2009 Category: Biology Authors: Ernesto Freire Source Type: journals

Antimicrobial Properties of Brevinin-2-Related Peptide and its Analogs: Efficacy Against Multidrug-Resistant Acinetobacter baumanniiEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Brevinin-2 related peptide (B2RP; GIWDTIKSMG10KVFAGKILQN20L.NH2), first isolated from skin secretions of the mink frog Lithobates septentrionalis, shows broad-spectrum antimicrobial activity but its therapeutic potential is limited by moderate hemolytic activity. The peptide adopts an [alpha]-helical conformation in a membrane-mimetic solvent but amphipathicity is low. Increasing amphipathicity together with hydrophobicity by the substitutions Lys16[rarr]Leu and Lys16[rarr]Ala increased hemolytic activity approximately fivefold without increasing antimicrobial potency. The substitution Leu18[rarr]Lys increased both cationi...
Source: Chemical Biology and Drug Design - September 27, 2009 Category: Biology Authors: J. Michael Conlon, Eman Ahmed, Eric Condamine Source Type: journals

Analysis of Flavonoid-Based Pharmacophores that Inhibit Aggrecanases (ADAMTS-4 and ADAMTS-5) and Matrix Metalloproteinases Through the Use of Topologically Constrained Peptide SubstratesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Polyphenolic natural products from green tea and red wine have been identified as metalloproteinase inhibitors. Members from the flavonoid and stilbene families found to possess metalloproteinase inhibitory activities include ([minus])-epigallocatechin gallate, ([minus])-epicatechin gallate and piceatannol, but their minimally active pharmacophores have not been evaluated. The present study has examined compounds that are structural components of or structurally related to ([minus])-epigallocatechin gallate, ([minus])-epicatechin gallate and piceatannol for inhibition of aggrecanases and four representative matrix metallop...
Source: Chemical Biology and Drug Design - September 27, 2009 Category: Biology Authors: Mare Cudic, Gayle D. Burstein, Gregg B. Fields, Janelle Lauer-Fields Source Type: journals

Antibacterial Activity, Quantitative Structure–Activity Relationship and Diastereoselective Synthesis of Isoxazolidine Derivatives Via 1,3-Dipolar Cycloaddition of d-glucose Derived Nitrone with OlefinEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The diastereoselectivity of the intermolecular 1,3-dipolar cycloaddition reaction of d-glucose-derived nitrones with both cyclic and acyclic dipolarophiles were studied. The reaction of nitrone with acyclic dipolarophiles resulted in the formation of the endo adduct exclusively whereas with cyclic dipolarophiles endo adduct was obtained as the major product. Antibacterial activity was evaluated for these eighteen isoxazolidine derivatives against Staphylococcus aureus NCIM5021, Escherichia coli NCIM 2931 and Pseudomonas aeruginosa NCIM 5029 by twofold dilution technique using resazurin as the indicator dye. Quantitative st...
Source: Chemical Biology and Drug Design - September 27, 2009 Category: Biology Authors: Munusamy Damodiran, Ponnurengan Malliappan Sivakumar, Rathnasabapathy SenthilKumar, Duraisamy Muralidharan, Bandara Venkata Narasimha Phani Kumar, Mukesh Doble, Paramasivan Thirumalai Perumal Source Type: journals

Molecular Shape Analysis of Antioxidant and Squalene Synthase Inhibitory Activities of Aromatic Tetrahydro-1,4-oxazine DerivativesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We have developed quantitative structure[ndash]activity relationship models for a series of hetero aromatic tetrahydro-1,4-oxazine derivatives exhibiting antioxidant as well as squalene synthase inhibitory activities using genetic function approximation and genetic partial least squares regression techniques. The independent variables used for the model development include descriptors belonging to various categories, viz. molecular shape analysis descriptors, Jurs spatial descriptors, shadow indices, electronic parameters and quantum chemical descriptors (Mulliken charges of the common atoms shared by the 22 oxazine deriva...
Source: Chemical Biology and Drug Design - September 27, 2009 Category: Biology Authors: Kunal Roy, Indrani Mitra, Achintya Saha Source Type: journals

Calendar of Events – November 2009Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Chemical Biology and Drug Design)
Source: Chemical Biology and Drug Design - September 22, 2009 Category: Biology Source Type: journals

Dimethylthiazolidine Carboxylic Acid as a Rigid P3 Unit in Inhibitors of Serine Proteases: Application to Two Targets†Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Serine proteases are a very large class of enzymes, many of which represent important targets for therapeutic agents against a wide variety of disease states. The similarity in active site architecture for these proteases has often allowed inhibitor design strategies for a particular target to be successfully applied to other enzymes in the class. In many cases, the presence of a bulky P3 amino acid residue in peptide-based inhibitors is central to conferring an extended peptide conformation, critical to binding of the ligands to serine protease active sites. The dimethylthiazolidine carboxylic acid 'residue' was found to ...
Source: Chemical Biology and Drug Design - September 21, 2009 Category: Biology Authors: Stephen H. Kawai, Norman Aubry, Jean-Simon Duceppe, Montse Llinàs-Brunet, Steven R. LaPlante Source Type: journals

Calendar of Events – October 2009Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Chemical Biology and Drug Design)
Source: Chemical Biology and Drug Design - September 8, 2009 Category: Biology Tags: Calendar of Events & #x2013; October 2009 Source Type: journals

Quantitative Structure–Activity Relationship Models for Predicting Biological Properties, Developed by Combining Structure- and Ligand-Based Approaches: An Application to the Human Ether-a-go-go-Related Gene Potassium Channel InhibitionEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
A strategy for developing accurate quantitative structure[ndash]activity relationship models enabling predictions of biological properties, when suitable knowledge concerning both ligands and biological target is available, was tested on a data set where molecules are characterized by high structural diversity. Such a strategy was applied to human ether-a-go-go-related gene K+ channel inhibition and consists of a combination of ligand- and structure-based approaches, which can be carried out whenever the three-dimensional structure of the target macromolecule is known or may be modeled with good accuracy. Molecular conform...
Source: Chemical Biology and Drug Design - September 8, 2009 Category: Biology Authors: Alessio Coi, Ilaria Massarelli, Marilena Saraceno, Niccolò Carli, Lara Testai, Vincenzo Calderone, Anna Maria Bianucci Tags: Research Articles Source Type: journals

Antibiotic Resistance in Bacteria: Novel Metalloenzyme InhibitorsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
[beta]-Lactam antibiotics are among the most important drugs used to fight bacterial infection. Overuse and misuse of [beta]-lactam antibiotics has caused the evolution of resistance mechanisms, allowing pathogenic bacteria to survive antibiotic treatment. The major source of resistance to [beta]-lactam antibiotics occurs through production of enzymes called [beta]-lactamases capable of catalyzing hydrolysis of the [beta]-lactam rings in these drug compounds. The metallo-[beta]-lactamases have become a major threat due to their broad substrate specificities; there are no clinically useful inhibitors for these metalloenzyme...
Source: Chemical Biology and Drug Design - September 8, 2009 Category: Biology Authors: Sung-Kun Kim, Cynthe L. Sims, Susan E. Wozniak, Stephanie H. Drude, Dustin Whitson, Robert W. Shaw Tags: Research Articles Source Type: journals

Small Molecule DnaK Modulators Targeting the β-DomainEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The molecular chaperone DnaK is essential for the survival of bacterial pathogens in the hostile environment of the host. Hence, it is in principle a promising target for drug design but for which no current inhibitors are available apart from certain antimicrobial peptides. To this end, we have screened libraries of small molecules for their ability to interact with the substrate-binding domain of DnaK. The most promising hit from the screen was synthesized and along with its analogs subjected to further assays to determine their binding affinity and ability to interfere with bacterial growth. This work resulted in the id...
Source: Chemical Biology and Drug Design - August 20, 2009 Category: Biology Authors: Cellitti Jason, Ziming Zhang, Si Wang, Bainan Wu, Hongbin Yuan, Patty Hasegawa, Donald G. Guiney, Maurizio Pellecchia Source Type: journals

Cyclic Opioid Peptide Agonists and Antagonists Obtained Via Ring-Closing MetathesisEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The opioid peptide H-Tyr-c[D-Cys-Phe-Phe-Cys]NH2 cyclized via a methylene dithiother is a potent and selective [mu] opioid agonist (Przydial M.J. et al., J Peptide Res, 66, 2005, 255). Dicarba analogues of this peptide with Tyr, 2'6'-dimethyltyrosine (Dmt), 3-[2,6-dimethyl-4-hydroxyphenyl)propanoic acid (Dhp) or (2S)-2-methyl-3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid [(2S)-Mdp] in the 1-position were prepared. The peptides were synthesized on solid-phase by substituting d-allylglycine and (2S)-2-amino-5-hexenoic acid in position 2 and 5, respectively, followed by ring-closing metathesis. Mixtures of cis and trans isom...
Source: Chemical Biology and Drug Design - August 19, 2009 Category: Biology Authors: Irena Berezowska, Carole Lemieux, Nga N. Chung, Brian C. Wilkes, Peter W. Schiller Source Type: journals

Evaluation of New Indole and Bromoindole Derivatives as pp60c-Src Tyrosine Kinase InhibitorsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
A series of N-benzyl-indole-3-imine-, amine derivatives and their 5-bromo congeners were synthesized and their biological activity were evaluated against the pp60c-Src tyrosine kinase target. To afford the imine derivatives, aldehydes were reacted with substituted benzylamines and the corresponding amine derivatives were obtained by NaBH4 reduction of these imines. Except insoluble N-benzyl-indole-3-imine derivatives, all the derivatives showed some activity against the kinase target. Screening of these compounds for their biological activity revealed that among N-benzyl-indole derivatives, those bearing 5-bromo substituti...
Source: Chemical Biology and Drug Design - August 19, 2009 Category: Biology Authors: Zühal Kılıç, Yasemin G. İşgör, Süreyya Ölgen Source Type: journals

Antiherpetic Properties of Acyclovir 5'-Hydrogenphosphonate and the Mutation Analysis of Herpes Virus Resistant StrainsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we continued to study antiherpetic properties of acyclovir 5'-hydrogenphosphonate (Hp-ACV) in cell cultures and animal models. Hp-ACV was shown to inhibit the development of herpetic infection in mice induced by the HSV-1/L2 strain. The compound suppressed replication of both ACV-sensitive HSV-1/L2 and ACV-resistant HSV-1/L2/R strains in Vero cell culture. Viral population resistant to Hp-ACV (HSV-1/L2/RHp-ACV) was developed much slower than ACV-resistant population. The analysis of Hp-ACV-resistant clones isolated from the HSV-1/L2/RHp-ACV population demonstrated their partial cross-resistance to ACV. The m...
Source: Chemical Biology and Drug Design - August 18, 2009 Category: Biology Authors: Anna A. Gus'kova, Mikhail Yu. Skoblov, Anna N. Korovina, Maxim V. Yasko, Inna L. Karpenko, Marina K. Kukhanova, Valeria L. Andronova, George A. Galegov, Yuri S. Skoblov Source Type: journals

Antimalarial Activity of the Novel Quinoline/6-Thiopurine Conjugate in Gallus gallus Linnaeus, Infected Experimentally by Plasmodium (Novyella) juxtanucleareEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This study aimed to evaluate the 4-(6'-thiopurine)-7-chloroquinoline, a novel quinoline/6-thiopurine conjugate, for the treatment of Gallus gallus experimentally infected with Plasmodium juxtanucleare, an avian malaria agent. The avian group treated with 4-(6'-thiopurine)-7-chloroquinoline showed a significative parasite clearance and maintained a low level of parasitaemia, when compared with the untreated control group and to the chloroquine treated avian group. (Source: Chemical Biology and Drug Design)
Source: Chemical Biology and Drug Design - August 18, 2009 Category: Biology Authors: Usha Vashist, Rafael Carvalhaes, Marta D'agosto, Adilson David da Silva Source Type: journals

Quantitative Structure–Activity Relationship Studies on 2-Amino-6-arylsulfonylbenzonitriles as Human Immunodeficiency Viruses Type 1 Reverse Transcriptase Inhibitors Using Descriptors Obtained from Substituents and Whole Molecular StructuresEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The human immunodeficiency viruses type 1 reverse transcriptase is a major target for drug development. Inhibition of this enzyme has been one of the primary therapeutic strategies in suppressing the replication of human immunodeficiency viruses type 1. A series of 2-amino-6-arylsulfonylbenzonitrile derivatives was subjected to quantitative structure[ndash]activity relationship analysis. The newly proposed substituent electronic descriptors were investigated for quantitative structure[ndash]activity relationship modeling of the compounds and a comparison was made with the conventional molecular descriptors. Two chemometric...
Source: Chemical Biology and Drug Design - August 18, 2009 Category: Biology Authors: Bahram Hemmateenejad, Razieh Sabet, Afshin Fassihi Source Type: journals

Synthesis and SAR Study of Opioid Receptor Ligands: Mono- and Bis-IndolomorphinansEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Mono- and bis-indolomorphinans were synthesized through a multi-step synthetic approach from the alkaloid, thebaine, to further explore the C-ring SAR (structure-activity relationship) of morphinan scaffold. Both mono-indoles displayed good binding affinity and selectivity for the [delta] receptor, with compound 6b possessed the highest Ki value of 1.45 nm at this receptor. Bisindolomorphinans 7a,b did not have appreciable affinity for both [delta] and [kappa] receptors, but moderate binding at the [mu] receptor was observed. Functional assays indicated that the newly synthesized mono-indole 6b was [delta]-agonist, opposit...
Source: Chemical Biology and Drug Design - August 18, 2009 Category: Biology Authors: Fuying Li, Chenlei Yin, Jie Chen, Jinggen Liu, Xin Xie, Ao Zhang Source Type: journals

The Influence of Opioids on Urokinase Plasminogen Activator on Protein and mRNA Level in MCF-7 Breast Cancer Cell LineEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we have determined the effect of [mu]-opioid receptor agonists and antagonists on the urokinase plasminogen activator secretion in MCF-7 cell line. It was shown that [mu]-opioid receptor agonists, such as morphine and endomorphins, greatly stimulate urokinase plasminogen activator secretion, while naloxone and MOR-selective antagonists elicit the opposite effect. The same tendency was observed also on the urokinase plasminogen activator mRNA level. However, neither agonists nor antagonists had any effect on proliferation of MCF-7 cells. The findings reported in this study may be useful in designing further e...
Source: Chemical Biology and Drug Design - August 18, 2009 Category: Biology Authors: Katarzyna Gach, Janusz Szemraj, Jakub Fichna, Mariola Piestrzeniewicz, Dick S. Delbro, Anna Janecka Source Type: journals

Discovery of 1-[1-(1-Methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole: Integrated Drug-Design and Structure–Activity Relationships for Orally Potent, Metabolically Stable and Potential-Risk Reduced Novel Non-Peptide Nociceptin/Orphanin FQ Receptor Agonist as Antianxiety Drug‡Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Anxiety disorders, caused by continuous or acute stress or fear, have been highly prevailing psychiatric disorders. For the acute treatment of the disorders, benzodiazepines have been widely used despite having liabilities that limit their utility. Alternatively, endogenous nociceptin/orphanin FQ and nociceptin/orphanin FQ peptide receptor (or opioid-receptor-like-1 receptor) have important roles in the integration of emotional components, e.g. anxiolytic activity is the key behavioral action of nociceptin/orphanin FQ in brain. In our preceding study, various structurally novel 1,2-disubstituted benzimidazole derivatives w...
Source: Chemical Biology and Drug Design - August 18, 2009 Category: Biology Authors: Shigeo Hayashi, Akiko Hirao, Hiroshi Nakamura, Kenzo Yamamura, Kunihiko Mizuno, Hiroyo Yamashita Source Type: journals

High-Content Analysis of Cancer-Cell-Specific Apoptosis and Inhibition of in Vivo Angiogenesis by Synthetic (−)-Pironetin and AnalogsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The natural product ([minus])-pironetin is a structurally simple small molecule microtubule-perturbing agent whose biological activities appear to be exquisitely dependent on defined stereochemistry and the presence of an eletrophilic [alpha],[beta]-unsaturated lactone moiety. We used alkaloid-catalyzed acyl halide-aldehyde cyclocondensation reactions in asymmetric total syntheses of ([minus])-pironetin and three synthetic analogs, and evaluated their biological activities by high-content analysis in cell culture and in a zebrafish model. Synthetic ([minus])-pironetin and 2,3-dihydro-3-hydroxypironetin caused mitotic arres...
Source: Chemical Biology and Drug Design - August 17, 2009 Category: Biology Authors: Andreas Vogt, Peter A. McPherson, Xiaoqiang Shen, Raghavan Balachandran, Guangyu Zhu, Brianne S. Raccor, Scott G. Nelson, Michael Tsang, Billy W. Day Source Type: journals

Calendar of Events – September 2009Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Chemical Biology and Drug Design)
Source: Chemical Biology and Drug Design - August 16, 2009 Category: Biology Tags: Calendar of Events & #x2013; September 2009 Source Type: journals

Antiproliferative Activity Against MCF-7 Breast Cancer Cells by Diamino-Triazaspirodiene AntifolatesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This study demonstrated the potential lead of the diamino-triazaspirodienes in anticancer chemotherapeutical agents' discovery. (Source: Chemical Biology and Drug Design)
Source: Chemical Biology and Drug Design - August 16, 2009 Category: Biology Authors: Xiang Ma, Renee Ser-Peng Woon, Paul Chi-Lui Ho, Wai-Keung Chui Tags: Research Letters Source Type: journals

Which Carbonic Anhydrases are Targeted by the Antiepileptic Sulfonamides and Sulfamates?Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Zonisamide, sulthiame, and topiramate, clinically used antiepileptics are inhibitors of mammalian carbonic anhydrase isoforms I[ndash]XIV, indiscriminately inhibiting with variable efficacy all the catalytically active isoforms present in mammals. However, it is not clear which carbonic anhydrase isozymes might be responsible for the anticonvulsant activity of such sulfonamide/sulfamate drugs. We examine here the full inhibition profile against all mammalian carbonic anhydrases of the above antiepileptic drugs together with two investigational, structurally related sulfonamides, one of which is and the other is not an anti...
Source: Chemical Biology and Drug Design - August 16, 2009 Category: Biology Authors: Giuseppina De Simone, Andrea Scozzafava, Claudiu T. Supuran Tags: Research Letters Source Type: journals

Structure Activity Relationship of Antiproliferative Agents using Multiple Linear RegressionEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
With cancer-related fatalities being the second leading cause of death in the USA, understanding the activity of effective chemotherapeutic agents is critical to addressing prostate and other cancers. Celecoxib, an FDA-approved drug for the treatment of colon tumors, has been used successfully as a lead compound in the development of antiproliferative agents. The ability of celecoxib to inhibit the development and progression of tumors has been connected to a number of mechanisms of actions that are both dependent on and independent of its cyclooxygenase-2 activity. A structure-based approach has been employed to develop a...
Source: Chemical Biology and Drug Design - August 16, 2009 Category: Biology Authors: Leyte L. Winfield, Tasha R. Inniss, Dayle M. Smith Tags: Research Letters Source Type: journals

One-Pot Synthesis of Highly Functionalized Seleno Amino Acid DerivativesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We herein provide a new and rapid protocol to generate derivatives of seleno amino acid, including methyl selenocysteine, selenomethionine, and selenocystine. Applying the isocyanide-based multicomponent reaction Ugi-4C-5C reaction, we show that each of the commercially available seleno amino acids are good substrate for these reactions and can be used together with complementary oxocomponents and isocyanides to generate highly diverse functionalized selenium-containing compounds. These compounds might become useful tools for applications in chemical biology to elucidate the role of selenium in biochemistry. (Source: Chemi...
Source: Chemical Biology and Drug Design - August 16, 2009 Category: Biology Authors: Haixia Liu, Alexander Dömling Tags: Research Letters Source Type: journals

Disubstituted 4(3H) Quinazolones: A Novel Class of Antitumor AgentsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
A series of disubstituted 4(3H) quinazolines were designed for potential application in tumors. Firstly, N-benzoyl anthranilic acid is formed, which undergoes cyclization in the presence of pyridine. Subsequently, nucleophilic attack by semicarbazide on the carbonyl carbon gives 2-substituted 3-carbamido 4(3H) quinazolones, which gives final compound with appropriate substitution. The final as well as intermediate products were confirmed by NMR, FT-IR, and mass spectrometry. In vitro toxicity was performed with different cell lines and showed that the connection of hydrophilic styryl to quinazoline moiety increases its eff...
Source: Chemical Biology and Drug Design - August 16, 2009 Category: Biology Authors: Vikas Srivastava, Anand Mohan Srivastava, Anjani K. Tiwari, Rakesh Srivastava, Rajbala Sharma, Himanshu Sharma, Vinay K. Singh Tags: Research Articles Source Type: journals

Binding Orientations, QSAR, and Molecular Design of Thiophene Derivative InhibitorsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
A theoretical study on binding orientations and quantitative structure[ndash]activity relationship of thiophene derivatives as inhibitors towards tubulin has been carried out by using the docking analysis and the comparative molecular field analysis. The appropriate binding orientations and conformations of these compounds interacting with tubulin were revealed by docking study; and a 3D-quantitative structure[ndash]activity relationship model showing significant statistical quality and satisfying predictive ability was established, in which the correlation coefficient (R2) and cross-validation coefficient (q2) are 0.949 a...
Source: Chemical Biology and Drug Design - August 16, 2009 Category: Biology Authors: Si Yan Liao, Tao Ju Chen, Ti Fang Miao, Li Qian, Kang Cheng Zheng Tags: Research Articles Source Type: journals

Synthesis and Biological Applications of Imidazolium-Based Polymerized Ionic Liquid as a Gene Delivery VectorEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The encouraging results of preliminary toxicological studies on imidazolium-based ionic liquids provide good opportunities for the development of ionic liquids in biomedical applications. In this work, the polymerized ionic liquid poly[3-butyl-1-vinylimidazolium L-proline salt] has been synthesized as a gene vector. The interaction of poly[3-butyl-1-vinylimidazolium L-proline salt] with DNA was studied by agarose gel electrophoresis. The cell viability was determined through PI (propidium iodine) staining and flow cytometry, showing marginal toxicity toward the cells examined. The transfection efficiency was evaluated thro...
Source: Chemical Biology and Drug Design - August 16, 2009 Category: Biology Authors: Yuanyuan Zhang, Xiang Chen, Jingbo Lan, Jingsong You, Lijuan Chen Tags: Research Articles Source Type: journals

Synthesis and Antibacterial Activity of a Series of α-Substituted Acetylpiperazinyl OxazolidinonesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
A series of oxazolidinone derivatives with [alpha]-substituted acetylpiperazinyl groups were prepared. Their in vitro antibacterial activities were studied against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecalis. The compounds with chloroacetyl-piperazinyl or dichloroacetyl-piperazinyl group were found to have superior antibacterial activities to linezolid against most of tested Gram-positive pathogens. The compounds with propionylpiperaziny or fluoroacetylpiperazinyl group were found to have comparable antibacterial...
Source: Chemical Biology and Drug Design - August 16, 2009 Category: Biology Authors: Xiao-Jun Wang, Guang-Jian Du, Shuang-Qi Zhao, Ming Yan, Lian-Quan Gu Tags: Research Articles Source Type: journals