Abstract:
:The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRP) is a crucial and unique component of the HCV RNA replication machinery and a validated target for drug discovery. Multiple crystal structures of NS5B inhibitor complexes have facilitated the identification of novel compound scaffolds through in silico analysis. With the goal of discovering new NS5B inhibitor leads, HCV NS5B crystal structures bound with inhibitors in the palm and thumb allosteric pockets in combination with ligands with known inhibitory potential were explored for a comparative pharmacophore analyses. The energy-based and 3D-QSAR-based pharmacophore models were validated using enrichment analysis, and the six models thus developed were employed for high-throughput virtual screening and docking to identify nonpeptidic leads. The hits derived at each stage were analyzed for diversity based on the six pharmacophore models, followed by molecular docking and filtering based on their interaction with amino acids in the NS5B allosteric pocket and 3D-QSAR predictions. The resulting 10 hits displaying diverse scaffold were then screened employing biochemical and cell-based NS5B and anti-HCV inhibition assays. Of these, two molecules H-5 and H-6 were the most promising, exhibiting IC50 values of 28.8 and 47.3 μM against NS5B polymerase and anti-HCV inhibition of 96% and 86% at 50 μM, respectively. The identified leads comprised of benzimidazole (H-5) and pyridine (H-6) scaffolds thus constitute prototypical molecules for further optimization and development as NS5B inhibitors.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Therese PJ,Manvar D,Kondepudi S,Battu MB,Sriram D,Basu A,Yogeeswari P,Kaushik-Basu Ndoi
10.1021/ci400644rsubject
Has Abstractpub_date
2014-02-24 00:00:00pages
539-52issue
2eissn
1549-9596issn
1549-960Xjournal_volume
54pub_type
杂志文章abstract::Virtual screening is routinely used to discover new ligands and in particular new ligand chemotypes for G protein-coupled receptors (GPCRs). To prepare for a virtual screen, we often tailor a docking protocol that will enable us to select the best candidates for further screening. To aid this, we created GPCR-Bench, a...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.5b00660
更新日期:2016-04-25 00:00:00
abstract::Curvularia lunata is a dark pigmented fungus that is the causative agent of several diseases in plants and in both immunodeficient and immunocompetent patients. 1,8-Dihydroxynaphthalene-melanin is found in the cell wall of C. lunata and is believed to be the important virulence factor of dematiaceous fungi. Trihydroxy...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci2001499
更新日期:2011-07-25 00:00:00
abstract::In this study, we tried to establish a general scheme to create a model that could predict the affinity of small compounds to their target proteins. This scheme consists of a search for ligand-binding sites on a protein, a generation of bound conformations (poses) of ligands in each of the sites by docking, identifica...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci800313h
更新日期:2009-04-01 00:00:00
abstract::Fragment complementation is gaining an increasing impact as a nonperturbing method to probe noncovalent interactions within protein supersecondary structures. In this study, the fast Fourier transform rigid-body docking algorithm ZDOCK has been employed for in silico reconstitution of the calcium binding protein calbi...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci0501995
更新日期:2005-09-01 00:00:00
abstract::Discovery of new antibacterial agents is a never-ending task of medicinal chemistry. Every new drug brings significant improvement to patients with bacterial infections, but prolonged usage of antibacterials leads to the emergence of resistant strains. Therefore, novel active structures with new modes of action are re...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.9b00436
更新日期:2019-11-25 00:00:00
abstract::We report the development of homology models of dopamine (D(2), D(3), and D(4)), serotonin (5-HT(1B), 5-HT(2A), 5-HT(2B), and 5-HT(2C)), histamine (H(1)), and muscarinic (M(1)) receptors, based on the high-resolution structure of the beta(2)-adrenergic receptor. The homology models were built and refined using Prime. ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci900444q
更新日期:2010-04-26 00:00:00
abstract::A comprehensive safety evaluation of chemicals should require toxicity assessment in both the aquatic and terrestrial test species. Due to the application practices and nature of chemical pesticides, the avian toxicity testing is considered as an essential requirement in the risk assessment process. In this study, tre...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.5b00139
更新日期:2015-07-27 00:00:00
abstract::Peptide libraries allow researchers to quickly find hundreds of peptide sequences with a desired property. Currently, the large amount of data generated from peptide libraries is analyzed by hand, where researchers search for repeating patterns in the peptide sequences. Such patterns are called motifs. In this work, w...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci300484q
更新日期:2013-02-25 00:00:00
abstract::The recognition of peptide/MHC by T-cell receptors is one of the most important interactions in the adaptive immune system. A large number of computational studies have investigated the structural dynamics of this interaction. However, to date only limited attention has been paid to differences between the dynamics of...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.5b00511
更新日期:2016-01-25 00:00:00
abstract::Template CoMFA, a novel alignment methodology for training or test set structures in 3D-QSAR, is introduced. Its two most significant advantages are its complete automation and its ability to derive a single combined model from multiple structural series affecting a biological target. Its only two inputs are one or mo...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci400696v
更新日期:2014-02-24 00:00:00
abstract::Physicochemical atomic stereodescriptors (PAS) were implemented that represent the chirality of an atomic chiral center on the basis of empirical physicochemical properties of the ligands. The ligands are ranked according to a specific property, and the chiral center takes an S/R-like descriptor relative to that prope...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci600235w
更新日期:2006-11-01 00:00:00
abstract::The viral NS5B RNA-dependent RNA-polymerase (RdRp) is one of the best-studied and promising targets for the development of novel therapeutics against hepatitis C virus (HCV). Allosteric inhibition of this enzyme has emerged as a viable strategy toward blocking replication of viral RNA in cell based systems. Herein, we...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci9004749
更新日期:2010-04-26 00:00:00
abstract::Herein we present the VMD Store, an open-source VMD plugin that simplifies the way that users browse, discover, install, update, and uninstall extensions for the Visual Molecular Dynamics (VMD) software. The VMD Store obtains data about all the indexed VMD extensions hosted on GitHub and presents a one-click mechanism...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.9b00739
更新日期:2019-11-25 00:00:00
abstract::Angiotensin II type 1 receptor (AT1R) is the principal regulator of blood pressure in humans. The overactivation of AT1R by the stimulation of angiotensin II would result in high blood pressure. To prevent hypertension, nonpeptide "sartan" drugs, such as valsartan (VST), have been developed to competitively block the ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.8b00364
更新日期:2018-10-22 00:00:00
abstract::The programs Phase and Catalyst HypoGen are compared for their performance in determining three-dimensional quantitative structure-activity relationships. Eight sets of compounds with measured activity were collected from the public literature and partitioned into suitable training and test sets by an automated proced...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci7000082
更新日期:2007-05-01 00:00:00
abstract::Distribution patterns of 8411 compounds from 240 Chinese herbs were analyzed in relation to the herbal categories of traditional Chinese medicine (TCM), using Random Forest (RF) and self-organizing maps (SOM). RF was used first to construct TCM profiles of individual compounds, which describe their affinities for 28 m...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci700155t
更新日期:2007-11-01 00:00:00
abstract::In this account, a rapid retrosynthesis-based scoring method for the assessment of synthetic accessibility of drug-like molecules, called RASA (Retrosynthesis-based Assessment of Synthetic Accessibility) is devised. RASA first constructs a synthesis tree for the target molecule based on retrosynthetic analysis; in thi...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci100216g
更新日期:2011-10-24 00:00:00
abstract::Class II fructose-1,6-bisphosphate aldolases (FBA-II) are attractive new targets for the discovery of drugs to combat invasive fungal infection, because they are absent in animals and higher plants. Although several FBA-II inhibitors have been reported, none of these inhibitors exhibit antifungal effect so far. In thi...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.6b00763
更新日期:2017-06-26 00:00:00
abstract::We present an algorithm, ReFlex3D, for the refinement of flexible molecular alignments based on their three-dimensional shape and electrostatic properties. The algorithm is designed to be used with fast conformer generators to refine an initial overlay between two molecules and thus to obtain improved overlaps as judg...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.7b00618
更新日期:2018-04-23 00:00:00
abstract::Small-molecule protein docking is an essential tool in drug design and to understand molecular recognition. In the present work we introduce FlexAID, a small-molecule docking algorithm that accounts for target side-chain flexibility and utilizes a soft scoring function, i.e. one that is not highly dependent on specifi...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.5b00078
更新日期:2015-07-27 00:00:00
abstract::We introduce the statistics behind a novel type of SAR analysis named "nonadditivity analysis". On the basis of all pairs of matched pairs within a given data set, the approach analyzes whether the same transformations between related molecules have the same effect, i.e., whether they are additive. Assuming that the e...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.9b00631
更新日期:2019-09-23 00:00:00
abstract::The present study focuses on the determination of the biologically significant N-acetylneuraminic acid (NANA) drug binding interaction mechanism between bovine serum albumin (BSA) and human α-1 acid glycoprotein (HAG) using various optical spectroscopy and computational methods. The steady state fluorescence spectrosc...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.8b00558
更新日期:2019-01-28 00:00:00
abstract::In structure-based drug design, scoring functions are often employed to evaluate protein-ligand interactions. A variety of scoring functions have been developed so far, and thus, some objective benchmarks are desired for assessing their strength and weakness. The comparative assessment of scoring functions (CASF) benc...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.8b00545
更新日期:2019-02-25 00:00:00
abstract::Due to the importance of hot-spots (HS) detection and the efficiency of computational methodologies, several HS detecting approaches have been developed. The current paper presents new models to predict HS for protein-protein and protein-nucleic acid interactions with better statistics compared with the ones currently...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci500760m
更新日期:2015-05-26 00:00:00
abstract::Retrieving molecules with specific structural features is a fundamental requirement of today's molecular database technologies. Estimates claim the chemical space relevant for drug discovery to be around 10⁶⁰ molecules. This figure is many orders of magnitude larger than the amount of molecules conventional databases ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci400107k
更新日期:2013-07-22 00:00:00
abstract::The roles of chemical compounds in biological systems are now systematically analyzed by high-throughput experimental technologies. To automate the processing and interpretation of large-scale data it is necessary to develop bioinformatics methods to extract information from the chemical structures of these small mole...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci700006f
更新日期:2007-07-01 00:00:00
abstract::There is a renewed interest in computer-aided synthesis planning, where the vast majority of approaches require the application of retrosynthetic reaction templates. Here we introduce RDChiral, an open-source Python wrapper for RDKit designed to provide consistent handling of stereochemical information in applying ret...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.9b00286
更新日期:2019-06-24 00:00:00
abstract::The more that is known about human and other genome sequences and the correlation between gene expression and the course of a disease, the more evident it seems to be that DNA is chosen as a drug target instead of proteins which are built with the information encoded by DNA. According to this approach, small minor gro...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci600500v
更新日期:2007-07-01 00:00:00
abstract::Membrane transporters play a crucial role in determining fate of administered drugs in a biological system. Early identification of plausible transporters for a drug molecule can provide insights into its therapeutic, pharmacokinetic, and toxicological profiles. In the present study, predictive models for classifying ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.6b00508
更新日期:2017-03-27 00:00:00
abstract::The accurate prediction of the adsorption energies of unsaturated molecules on graphene in the presence of water is essential for the design of molecules that can modify its properties and that can aid its processability. We here show that a semiempirical MO method corrected for dispersive interactions (PM6-DH2) can p...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci5003729
更新日期:2014-08-25 00:00:00