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ABSTRACT: A system dynamics structure to characterize the link between technology and critical management decisions in the drug discovery process (DDP) is needed. The DDP includes many interacting feedback loops that impact decisions executed in early stages and that influence performance in later development stages. The complexity of the DDP and the absence of systemic perspective, contributes imprecision to decision-makers' own mental models, and limits their ability to generate decisions that provoke genuine process improvements. Hence, the emergence and use of new integrated technology- and knowledge-based approaches bridge to R&D concern at least early attrition rates, critical high-content chemical lead value identification and time delay reduction for the early phase DDP.
Drug Discovery Today 08/2008; 13(15-16):708-15. · 6.83 Impact Factor
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ABSTRACT: The existing literature suggests the Bayesian-Frequentist debate could soon be involved in the prioritization of hits from HTS campaigns. The Bayesian-Frequentist debate reflects two archetypical attitudes regarding the process of conducting scientific and technological research. This review article covers recent advances in statistical analyses, currently in use, for hit selection in the drug discovery process. The impact of decisions (e.g. attrition) executed at early stages in the drug discovery process influences HTS performance in later development stages. It shows that, as the high content value of the information from HTS campaigns increases over time, the two statistical approaches aim to provide similar answers, but they might not succeed.
Drug Discovery Today 07/2008; 13(11-12):536-42. · 6.83 Impact Factor
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ABSTRACT: Pentaerythritol and bis-pentaerythritol scaffolds were used for the preparation of first generation glycodendrimers bearing aryl alpha-D-mannopyranoside residues assembled using single-step Sonogashira and click chemistry. The carbohydrate precursors were built with either para-iodophenyl, propargyl, or 2-azidoethyl aglycones whereas the pentaerythritol moieties were built with terminal azide or propargyl groups, respectively. Cross-linking abilities of this series of glycodendrimers were first evaluated with the lectin from Canavalia ensiformis (Concanavalin A). Surface plasmon resonance measurements showed these two families of mannosylated clusters as the best ligands known to date toward Escherichia coli K12 FimH with subnanomolar affinities. Tetramer 4 had a K(d) of 0.45 nM. These clusters were 1000 times more potent than mannose for their capacity to inhibit the binding of E. coli to erythrocytes in vitro.
ChemMedChem 09/2007; 2(8):1190-201. · 3.15 Impact Factor
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ABSTRACT: SARS is a viral respiratory illness caused by a previously unrecognized coronavirus, called SARS-associated coronavirus (SARS-CoV). Because of the potential for a rapid spread of the disease, it is vitally important to identify drugs that effectively inhibit a known target of the SARS coronavirus. Because of its essential role in proteolytic processing, the main protease MPro, a cysteine protease, is considered an attractive target for antiviral drugs against SARS and other coronavirus infections. In this review, we will present both peptidic and non-peptidic inhibitors that have been designed against SARS MPro. The most challenging requirement in designing cysteine inhibitors is to obtain a selective non-covalent electrophilic isostere that can react with the catalytic nucleophile. Emphasis will be put on our recent results, both experimental and theoretical, in the search for potent wide-spectrum inhibitors. The antiviral activity of the octopeptide AVLQSGFR against SARS-associated coronavirus will be presented as well as the recent hits obtained from virtual high throughput screening (vHTS) based on the identification of six hydrogen bond pharmacophore points from KZ7088 docked into the active site of SARS MPro.
Current Computer - Aided Drug Design 08/2007; 3(3):191-200. · 1.76 Impact Factor
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ABSTRACT: A wide variety of proteins can bind high-mannose oligosaccharides and are broadly neutralizing against HIV-1. However, success in eliciting broadly neutralizing antibodies against HIV-1 has been limited to date. The rational design of an HIV-1 vaccine is based on the information gained through the structural analysis of antibodies complexed with their epitopes. Of particular interest to this review are the binding of mannosides to human monoclonal antibody 2G12 recognizing Man(9)GlcNAc(2) from HIV-1 gp120. It is widely recognized that T-cell-independent antigens carbohydrates are poorly immunogenic, and fail to induce memory. To increase the immunogenicity, carbohydrate antigens have to be coupled to a highly immunogenic carrier. The design of peptide carbohydrate mimotopes (mimetics of carbohydrate antigens) is one approach that is currently explored to elicit neutralizing antibodies. This work is concerned with existing structural data on Man(9)GlcNAc(2) as the most promising epitope (or glycotope). Structural analysis of various torsion angles of Man(9)GlcNAc(2) is explored. The focus is made primarily on the third variable region (V3 loop) of gp120 due to its crucial relevance for coreceptor usage, as a principal neutralizing determinant (PND), and for its conserved glycosylation sites N295, N302 and N332. Valuable structural information from glycosylation effects is taken into account for the development of a V3 loop rational structure-based vaccine strategy using N295 and N302 as potential conformational epitope.
Current Medicinal Chemistry 02/2007; 14(30):3232-42. · 4.86 Impact Factor
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ABSTRACT: This study presents the first QSAR model for Galectin-3 glycomimetic inhibitors based on docked structures to the carbohydrate recognition domain (CRD). Quantitative numerical methods such as PLS (Partial Least Squares) and ANN (Artificial Neural Networks) have been used and compared on QSAR models to establish correlations between molecular properties and binding affinity values (Kd). Training and validation of QSAR predictive models was performed on a master dataset consisting of 136 compounds. The molecular structures and binding affinities (Kd) (136 compounds) were obtained from the literature. To address the issue of dimensionality reduction, molecular descriptors were selected with PLS contingency approach, ANN, PCA (Principal Component Analysis) and GA (Genetic Algorithms) for the best predictive Galectin-3 binding affinity (Kd). Final sets comprising 56, 31 and 35 descriptors were obtained with PLS, PCA and ANN, respectively. The objective of this prototype QSAR model is to serve as a first guideline for the design of novel and potent Gal-3 selective inhibitors with emphasis on modification at both C-3' and at O-3 positions.
Medicinal Chemistry 10/2006; 2(5):481-9. · 1.50 Impact Factor
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ABSTRACT: Phase transfer catalyzed reaction was used for the high yielding synthesis of aryl 1-thio-beta-d-galacto- and lacto-pyranosides carrying a panel of substituents on the phenyl groups. Best galectin-1 inhibitors were simple p-nitrophenyl thiogalactoside 5a for the monosaccharide and o-nitrophenyl thiolactoside 6f or napthylsulfonyl lactoside 8c, both being 20 times better relative to natural ligands. Relative inhibitory properties as low as 2500 and 40 microM were observed, respectively. The electronic effects of the lactoside aglycons directly influenced the electrostatic potential at O-3, which was associated with the inhibitory potencies against galectin-1.
Bioorganic & Medicinal Chemistry Letters 04/2006; 16(6):1668-72. · 2.55 Impact Factor
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ABSTRACT: Since the outbreak of SARS (severe acute respiratory syndrome) in November 2002 in Southern China's Guangdong Province, considerable progress has been made in the development of drugs for SARS therapy. The present mini review is focused on the area of computer-aided drug discovery, i.e., the advances achieved mainly from the approaches of structural bioinformatics, pharmacophore modeling, molecular docking, peptide-cleavage site prediction, and other computational means. It is highlighted that the compounds C(28)H(34)O(4)N(7)Cl, C(21)H(36(O)5)N(6) and C(21)H(36)O(5)N(6) (Wei et al., Amino Acids, 2006, 31: 73-80), as well as KZ7088 (Chou et al. Biochem. Biophys. Res. Commun., 2003, 308: 148-151), a derivative of AG7088, might be the promising candidates for further investigation, and that the octapeptides ATLQAIAS and ATLQAENV, as well as AVLQSGFR, might be converted to effective inhibitors against the SARS enzyme. Meanwhile, how to modify these octapeptides based on the "distorted key" theory to make them become potent inhibitors is explicitly elucidated. Finally, a brief introduction is given for how to use computer-generated graphs to rapidly diagnose SARS coronavirus.
Current Medicinal Chemistry 02/2006; 13(27):3263-70. · 4.86 Impact Factor
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ABSTRACT: HIV-1 cell entry is mediated by sequential interactions of the envelope protein gp120 with the receptor CD4 and a coreceptor, usually CCR5 or CXCR4, depending on the individual virion. Considerable efforts on exploiting the HIV coreceptors as drug targets have led to the new class of coreceptor antagonists. While these antiretroviral drugs aim at preventing virus/coreceptor interaction by binding to host proteins, neutralizing antibodies directed against the coreceptor-binding sites on gp120 have attracted attention as possible vaccine candidates. However, both approaches are complicated by the multiple protective mechanisms of gp120 which allow for rapid escape from selective pressures exerted by drugs or antibodies. Thus, advances in rational drug and vaccine design rely heavily on improved insights into the relation between genotype and phenotype, the evolution of coreceptor usage, and, ultimately the structural biology of coreceptor usage and inhibition. The third variable (V3) loop of gp120, crucially involved in all these aspects, will be a major focus of this review.
Current Protein and Peptide Science 11/2005; 6(5):413-22. · 2.89 Impact Factor
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ABSTRACT: High throughput virtual screening is acknowledged as the initial means for identifying hit compounds that will be eventually transformed to leads or drug candidates. To improve quality of screening, it is essential to have powerful methods for the analysis of the compound databases. For this purpose, we have developed a novel and practical scoring function to assess the druggability of compounds. The proposed function consists of 12 metrics that take into account physical, chemical and structural properties as well as the presence of undesirable functional groups. We have applied this 12-metric scoring function to 44 different databases that include more than 3.8 million compounds, which are commercially available. The overall quality of each database was evaluated according to the score and rank measured by our 12-metric function. Our findings suggest that, the majority of compounds that do not satisfy druggable rules do so due to high molecular weight, high logP values and the presence of reactive functional groups.
Computational Biology and Chemistry 03/2005; 29(1):55-67. · 1.55 Impact Factor
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ABSTRACT: Severe acute respiratory syndrome (SARS) is a respiratory disease caused by a newly found virus, called SARS coronavirus. In this study, the cleavage mechanism of the SARS coronavirus main proteinase (Mpro or 3CLpro) on the octapeptide NH2-AVLQ downward arrowSGFR-COOH was investigated using molecular mechanics and quantum mechanics simulations based on the experimental structure of the proteinase. It has been observed that the catalytic dyad (His-41/Cys-145) site between domains I and II attracts the pi electron density from the peptide bond Gln-Ser, increasing the positive charge on C(CO) of Gln and the negative charge on N(NH) of Ser, so as to weaken the Gln-Ser peptide bond. The catalytic functional group is the imidazole group of His-41 and the S in Cys-145. Ndelta1 on the imidazole ring plays the acid-base catalytic role. Based on the "distorted key theory" [K.C. Chou, Anal. Biochem. 233 (1996) 1-14], the possibility to convert the octapeptide to a competent inhibitor has been studied. It has been found that the chemical bond between Gln and Ser will become much stronger and no longer cleavable by the SARS enzyme after either changing the carbonyl group CO of Gln to CH2 or CF2 or changing the NH of Ser to CH2 or CF2. The octapeptide thus modified might become an effective inhibitor or a potential drug candidate against SARS.
Analytical Biochemistry 03/2005; 337(2):262-70. · 3.00 Impact Factor
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ABSTRACT: The cleavage mechanism of severe acute respiratory syndrome (SARS) coronavirus main proteinase (M(pro) or 3CL(pro)) for the octapeptide AVLQSGFR is studied using molecular mechanics (MM) and quantum mechanics (QM). The catalytic dyad His-41 and Cys-145 in the active pocket between domain I and II seem to polarize the pi-electron density of the peptide bond between Gln and Ser in the octapeptide, leading to an increase of positive charge on C(CO) of Gln and negative charge on N(NH) of Ser. The possibility of enhancing the chemical bond between Gln and Ser based on the "distorted key" theory [Anal. Biochem. 233 (1996) 1] is examined. The scissile peptide bond between Gln and Ser is found to be solidified through "hybrid peptide bond" by changing the carbonyl group CO of Gln to CH(2) or CF(2). This leads to a break of the pi-bond system for the peptide bond, making the octapeptide (AVLQSGFR) a "distorted key" and a potential starting system for the design of anti SARS drugs.
Peptides 12/2004; 25(11):1857-64. · 2.43 Impact Factor
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ABSTRACT: In this paper we report detailed theoretical studies of formic acid–water clusters using a Gaussian implementation of Kohn–Sham density functional theory (DFT). Some MP2 calculations were made when necessary to make comparison. The newly developed Laplacian-dependent (LAP) functionals are extensively used although calculations with other traditional gradient-corrected functionals were also made for comparison. To assess our techniques we studied first the formic acid dimer. Good results for structures, vibrational frequencies and proton transfer barrier heights were achieved by the LAP functionals in contrary to other DFT methods, which usually give extremely low barrier heights. We obtained optimized structures of the formic acid–water clusters with up to 4 waters with many possible minimum energy states. The vibrational frequencies, successive hydration energy as well as the corresponding enthalpy were calculated. The interaction energy between formic acid and water was found to be larger than that of water–water. Ring-type structures are among the lowest in energy. Transition states were located for formic acid–water with various solvation patterns to study the effect of hydration on the proton transfer barrier. The transition state structures are of two fundamental types, i.e., a formic acid anion bound to H3O+- and H5O2+-centered structures, respectively. The proton transfer barrier is reduced by proper solvation of the transition states, notably to full and proper solvation of the hydrated proton units. © 2002 American Institute of Physics.
The Journal of Chemical Physics 04/2002; 116(14):6028-6038. · 3.33 Impact Factor
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ABSTRACT: Called by many as the biology's version of Swiss army knives, proteases cut long sequences of amino acids into fragments and
regulate most physiological processes. They are vitally important in life cycle and have become a main target for drug design.
This Chapter is focused on a special protease that plays a key role in replicating SARS (Severe Acute Respiratory Syndrome)
coronavirus, the culprit of SARS disease. The progresses reported here are mainly from various computational approaches, such
as structural bioinformatics, pharmacophore modelling, molecular docking, and peptide-cleavage site prediction, among others.
It is highlighted that the compounds C28H34O4N7Cl, C21H36O5N6 and C21H36O5N6, as well as KZ7088, a derivative of AG7088, might be the promising candidates for further investigation, and that the octapeptides
ATLQAIAS and ATLQAENV, as well as AVLQSGFR, might be converted to effective inhibitors against the SARS protease. Meanwhile,
how to modify these octapeptides based on the “distorted key” theory to make them become potent inhibitors is explicitly elucidated.
Also, a brief introduction is given for how to use computer-generated graphs to rapidly diagnose SARS coronavirus. Finally,
a step-by-step protocol guide is given on how to use ProtIdent, a web-server developed recently, to identify the proteases
and their types based on their sequence information alone. ProtIdent is a very user-friendly bioin-formatics tool that can
provide desired information for both basic research and drug discovery in a timely manner. With the avalanche of protein sequences
generated in the post-genomic age, it is particularly useful. ProtIdent is freely accessible to the public via the web-site
at http://www.csbio.sjtu.edu.cn/bioinf/Protease/.
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ABSTRACT: Pharmacophore modeling can provide valuable insight into ligand-receptor interactions. It can also be used in 3D (dimensional) database searching for potentially finding biologically active compounds and providing new research ideas and directions for drug-discovery projects. To stimulate the structure-based drug design against SARS (severe acute respiratory syndrome), a pharmacophore search was conducted over 3.6 millions of compounds based on the atomic coordinates of the complex obtained by docking KZ7088 (a derivative of AG7088) to SARS CoV M(pro) (coronavirus main proteinase), as reportedly recently (Chou, K. C.; Wei, D. Q.; Zhong, W. Z. Biochem. Biophys. Res. Commun. 2003, 308, 148-151). It has been found that, of the 3.6 millions of compounds screened, 0.07% are with the score satisfying five of the six pharmacophore points. Moreover, each of the hit compounds has been evaluated for druggability according to 13 metrics based on physical, chemical, and structural properties. Of the 0.07% compounds thus retrieved, 17% have a perfect score of 1.0; while 23% with one druggable rule violation, 13% two violations, and 47% more than two violations. If the criterion for druggability is set at a maximum allowance of two rule violations, we obtain that only about 0.03% of the compounds screened are worthy of further tests by experiments. These findings will significantly narrow down the search scope for potential compounds, saving substantial time and money. Finally, the featured templates derived from the current study will also be very useful for guiding the design and synthesis of effective drugs for SARS therapy.
Journal of Chemical Information and Computer Sciences 44(3):1111-22.
