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WIDOCK: a reactive docking protocol for virtual screening of covalent inhibitors

Here we present WIDOCK, a virtual screening protocol that supports the selection of diverse electrophiles as covalent inhibitors by incorporating ligand reactivity towards cysteine residues into AutoDock4. WIDOCK applies the reactive docking method (Backus et al. in Nature 534:570–574, 2016) and ext...

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Autores principales: Scarpino, Andrea, Petri, László, Knez, Damijan, Imre, Tímea, Ábrányi-Balogh, Péter, Ferenczy, György G., Gobec, Stanislav, Keserű, György M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904743/
https://www.ncbi.nlm.nih.gov/pubmed/33458809
http://dx.doi.org/10.1007/s10822-020-00371-5
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author Scarpino, Andrea
Petri, László
Knez, Damijan
Imre, Tímea
Ábrányi-Balogh, Péter
Ferenczy, György G.
Gobec, Stanislav
Keserű, György M.
author_facet Scarpino, Andrea
Petri, László
Knez, Damijan
Imre, Tímea
Ábrányi-Balogh, Péter
Ferenczy, György G.
Gobec, Stanislav
Keserű, György M.
author_sort Scarpino, Andrea
collection PubMed
description Here we present WIDOCK, a virtual screening protocol that supports the selection of diverse electrophiles as covalent inhibitors by incorporating ligand reactivity towards cysteine residues into AutoDock4. WIDOCK applies the reactive docking method (Backus et al. in Nature 534:570–574, 2016) and extends it into a virtual screening tool by introducing facile experimental or computational parametrization and a ligand focused evaluation scheme together with a retrospective and prospective validation against various therapeutically relevant targets. Parameters accounting for ligand reactivity are derived from experimental reaction kinetic data or alternatively from computed reaction barriers. The performance of this docking protocol was first evaluated by investigating compound series with diverse warhead chemotypes against KRAS(G12C), MurA and cathepsin B. In addition, WIDOCK was challenged on larger electrophilic libraries screened against OTUB2 and NUDT7. These retrospective analyses showed high sensitivity in retrieving experimental actives, by also leading to superior ROC curves, AUC values and better enrichments than the standard covalent docking tool available in AutoDock4 when compound collections with diverse warheads were investigated. Finally, we applied WIDOCK for the prospective identification of covalent human MAO-A inhibitors acting via a new mechanism by binding to Cys323. The inhibitory activity of several predicted compounds was experimentally confirmed and the labelling of Cys323 was proved by subsequent MS/MS measurements. These findings demonstrate the usefulness of WIDOCK as a warhead-sensitive, covalent virtual screening protocol. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10822-020-00371-5.
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spelling pubmed-79047432021-03-09 WIDOCK: a reactive docking protocol for virtual screening of covalent inhibitors Scarpino, Andrea Petri, László Knez, Damijan Imre, Tímea Ábrányi-Balogh, Péter Ferenczy, György G. Gobec, Stanislav Keserű, György M. J Comput Aided Mol Des Article Here we present WIDOCK, a virtual screening protocol that supports the selection of diverse electrophiles as covalent inhibitors by incorporating ligand reactivity towards cysteine residues into AutoDock4. WIDOCK applies the reactive docking method (Backus et al. in Nature 534:570–574, 2016) and extends it into a virtual screening tool by introducing facile experimental or computational parametrization and a ligand focused evaluation scheme together with a retrospective and prospective validation against various therapeutically relevant targets. Parameters accounting for ligand reactivity are derived from experimental reaction kinetic data or alternatively from computed reaction barriers. The performance of this docking protocol was first evaluated by investigating compound series with diverse warhead chemotypes against KRAS(G12C), MurA and cathepsin B. In addition, WIDOCK was challenged on larger electrophilic libraries screened against OTUB2 and NUDT7. These retrospective analyses showed high sensitivity in retrieving experimental actives, by also leading to superior ROC curves, AUC values and better enrichments than the standard covalent docking tool available in AutoDock4 when compound collections with diverse warheads were investigated. Finally, we applied WIDOCK for the prospective identification of covalent human MAO-A inhibitors acting via a new mechanism by binding to Cys323. The inhibitory activity of several predicted compounds was experimentally confirmed and the labelling of Cys323 was proved by subsequent MS/MS measurements. These findings demonstrate the usefulness of WIDOCK as a warhead-sensitive, covalent virtual screening protocol. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10822-020-00371-5. Springer International Publishing 2021-01-18 2021 /pmc/articles/PMC7904743/ /pubmed/33458809 http://dx.doi.org/10.1007/s10822-020-00371-5 Text en © The Author(s) 2021 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Scarpino, Andrea
Petri, László
Knez, Damijan
Imre, Tímea
Ábrányi-Balogh, Péter
Ferenczy, György G.
Gobec, Stanislav
Keserű, György M.
WIDOCK: a reactive docking protocol for virtual screening of covalent inhibitors
title WIDOCK: a reactive docking protocol for virtual screening of covalent inhibitors
title_full WIDOCK: a reactive docking protocol for virtual screening of covalent inhibitors
title_fullStr WIDOCK: a reactive docking protocol for virtual screening of covalent inhibitors
title_full_unstemmed WIDOCK: a reactive docking protocol for virtual screening of covalent inhibitors
title_short WIDOCK: a reactive docking protocol for virtual screening of covalent inhibitors
title_sort widock: a reactive docking protocol for virtual screening of covalent inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904743/
https://www.ncbi.nlm.nih.gov/pubmed/33458809
http://dx.doi.org/10.1007/s10822-020-00371-5
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