Comparative Evaluation of Covalent Docking Tools

Journal of Chemical Information and Modeling, Год журнала: 2018, Номер 58(7), С. 1441 - 1458

Опубликована: Июнь 11, 2018

Increased interest in covalent drug discovery led to the development of computer programs predicting binding mode and affinity inhibitors. Here we compare performance six docking tools, AutoDock4, CovDock, FITTED, GOLD, ICM-Pro, MOE, for reproducing experimental modes an unprecedently large diverse set complexes. It was found that 40–60% top scoring ligand poses are within 2.0 Å RMSD from mode. This rate showed program dependent increase achieved 50–90% when best among ten considered. is comparable noncovalent tools therefore suggests anchoring does not necessarily improve accuracy prediction. The effect various protein features on investigated. At level warhead chemistry, higher success Michael additions, nucleophilic additions substitutions than ring opening reactions disulfide formation. Increasing size flexibility generally affects pose predictions unfavorably, although ICM-Pro were be less sensitive up 35 heavy atoms. accessibility target cysteine tends result improved predictions. Docking show suggesting a target-dependent choice optimal tool. into Cys/Ala mutated proteins by Glide reproduced with only slightly lower at significantly computational expense did. Overall, our results highlight key factors influencing investigated they give guidelines selecting combination warheads, ligands, system Results also identify most important aspects considered developing protocols virtual screening ligands.

Язык: Английский

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Pharmacoinformatics and molecular dynamics simulation studies reveal potential covalent and FDA-approved inhibitors of SARS-CoV-2 main protease 3CL^pro

Journal of Biomolecular Structure and Dynamics, Год журнала: 2020, Номер 39(13), С. 4936 - 4948

Опубликована: Июнь 24, 2020

The SARS-CoV-2 was confirmed to cause the global pandemic of coronavirus disease 2019 (COVID-19). 3-chymotrypsin-like protease (3CLpro), an essential enzyme for viral replication, is a valid target combat SARS-CoV and MERS-CoV. In this work, we present structure-based study identify potential covalent inhibitors containing variety chemical warheads. targeted Asinex Focused Covalent (AFCL) library screened based on different reaction types were identified. addition, FDA-approved find candidates be repurposed against 3CLpro. A number compounds with significant docking scores These able establish bond (C–S) reactive thiol group Cys145 form favorable interactions residues lining substrate-binding site. Moreover, paritaprevir simeprevir from identified as mechanism dynamic stability binding between 3CLpro characterized by molecular dynamics (MD) simulations. are worthy further development COVID-19 drugs. Importantly, anti-hepatitis-C virus (HCV) drugs could ready clinical trials treat infected patients help curb COVID-19.

Язык: Английский

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A Survey of the Role of Nitrile Groups in Protein–Ligand Interactions

Future Medicinal Chemistry, Год журнала: 2018, Номер 10(23), С. 2713 - 2728

Опубликована: Дек. 1, 2018

In classical medicinal chemistry, nitrile groups were commonly considered as bioisosteres of carbonyl, hydroxyl and carboxyl groups, well halogen atoms. However, there is a lack in-depth understanding about the structural energetic characteristics in protein-ligand interactions. Here, we have surveyed Protein Data Bank ChEMBL databases with goal characterizing such interactions for nitrile-containing compounds. We discuss versatile roles improving binding affinities, give special attention to examples displacing mimicking binding-site waters by groups. expect that this review article will further inspire chemists exploit rationally structure-based drug design.

Язык: Английский

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Virtual screening web servers: designing chemical probes and drug candidates in the cyberspace

Briefings in Bioinformatics, Год журнала: 2020, Номер 22(2), С. 1790 - 1818

Опубликована: Фев. 25, 2020

The interplay between life sciences and advancing technology drives a continuous cycle of chemical data growth; these are most often stored in open or partially databases. In parallel, many different types algorithms being developed to manipulate objects associated bioactivity data. Virtual screening methods among the popular computational approaches pharmaceutical research. Today, user-friendly web-based tools available help scientists perform virtual experiments. This article provides an overview internet resources enabling supporting biology early drug discovery with main emphasis on web servers dedicated ligand small-molecule docking. survey first introduces some key concepts then presents recent easily accessible related target-fishing as well briefly discusses case studies enabled by services. Notwithstanding further improvements, already not only contribute design bioactive molecules assist repositioning but also generate new ideas explore hypotheses timely fashion while contributing teaching field development.

Язык: Английский

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What coronavirus 3C‐like protease tells us: From structure, substrate selectivity, to inhibitor design

Medicinal Research Reviews, Год журнала: 2021, Номер 41(4), С. 1965 - 1998

Опубликована: Янв. 18, 2021

Abstract The emergence of a variety coronaviruses (CoVs) in the last decades has posed huge threats to human health. Especially, ongoing pandemic coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome 2 (SARS‐CoV‐2) led more than 70 million infections and over 1.6 deaths worldwide past few months. None efficacious antiviral agents against CoVs have been approved yet. 3C‐like protease (3CL pro ) is an attractive target for intervention due its essential role processing polyproteins translated from viral RNA, conserved structural feature substrate specificity among spite sequence variation. This review focuses on all available crystal structures 12 CoV 3CL s their inhibitors, intends provide comprehensive understanding this multiple aspects including features, specificity, inhibitor binding modes, importantly, recapitulate similarity diversity different structure–activity relationship various types inhibitors. Such attempt could gain deep insight into inhibition mechanisms drive future structure‐based drug discovery targeting s.

Язык: Английский

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