Fragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A 2A adenosine receptor binding site

Abstract Fragment-based lead discovery is becoming an increasingly popular strategy for drug discovery. Fragment screening identifies weakly binding compounds that require optimization to become high-affinity leads. As design of leads from fragments is challenging, reliable computational methods to...

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Autores principales:	Pierre Matricon, Anirudh Ranganathan, Eugene Warnick, Zhan-Guo Gao, Axel Rudling, Catia Lambertucci, Gabriella Marucci, Aitakin Ezzati, Mariama Jaiteh, Diego Dal Ben, Kenneth A. Jacobson, Jens Carlsson
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/24c1cb3e575e44c6b3e9de6c28191221
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spelling	oai:doaj.org-article:24c1cb3e575e44c6b3e9de6c281912212021-12-02T11:52:56ZFragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A 2A adenosine receptor binding site10.1038/s41598-017-04905-02045-2322https://doaj.org/article/24c1cb3e575e44c6b3e9de6c281912212017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04905-0https://doaj.org/toc/2045-2322Abstract Fragment-based lead discovery is becoming an increasingly popular strategy for drug discovery. Fragment screening identifies weakly binding compounds that require optimization to become high-affinity leads. As design of leads from fragments is challenging, reliable computational methods to guide optimization would be invaluable. We evaluated using molecular dynamics simulations and the free energy perturbation method (MD/FEP) in fragment optimization for the A2A adenosine receptor, a pharmaceutically relevant G protein-coupled receptor. Optimization of fragments exploring two binding site subpockets was probed by calculating relative binding affinities for 23 adenine derivatives, resulting in strong agreement with experimental data (R2 = 0.78). The predictive power of MD/FEP was significantly better than that of an empirical scoring function. We also demonstrated the potential of the MD/FEP to assess multiple binding modes and to tailor the thermodynamic profile of ligands during optimization. Finally, MD/FEP was applied prospectively to optimize three nonpurine fragments, and predictions for 12 compounds were evaluated experimentally. The direction of the change in binding affinity was correctly predicted in a majority of the cases, and agreement with experiment could be improved with rigorous parameter derivation. The results suggest that MD/FEP will become a powerful tool in structure-driven optimization of fragments to lead candidates.Pierre MatriconAnirudh RanganathanEugene WarnickZhan-Guo GaoAxel RudlingCatia LambertucciGabriella MarucciAitakin EzzatiMariama JaitehDiego Dal BenKenneth A. JacobsonJens CarlssonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Pierre Matricon Anirudh Ranganathan Eugene Warnick Zhan-Guo Gao Axel Rudling Catia Lambertucci Gabriella Marucci Aitakin Ezzati Mariama Jaiteh Diego Dal Ben Kenneth A. Jacobson Jens Carlsson Fragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A 2A adenosine receptor binding site
description	Abstract Fragment-based lead discovery is becoming an increasingly popular strategy for drug discovery. Fragment screening identifies weakly binding compounds that require optimization to become high-affinity leads. As design of leads from fragments is challenging, reliable computational methods to guide optimization would be invaluable. We evaluated using molecular dynamics simulations and the free energy perturbation method (MD/FEP) in fragment optimization for the A2A adenosine receptor, a pharmaceutically relevant G protein-coupled receptor. Optimization of fragments exploring two binding site subpockets was probed by calculating relative binding affinities for 23 adenine derivatives, resulting in strong agreement with experimental data (R2 = 0.78). The predictive power of MD/FEP was significantly better than that of an empirical scoring function. We also demonstrated the potential of the MD/FEP to assess multiple binding modes and to tailor the thermodynamic profile of ligands during optimization. Finally, MD/FEP was applied prospectively to optimize three nonpurine fragments, and predictions for 12 compounds were evaluated experimentally. The direction of the change in binding affinity was correctly predicted in a majority of the cases, and agreement with experiment could be improved with rigorous parameter derivation. The results suggest that MD/FEP will become a powerful tool in structure-driven optimization of fragments to lead candidates.
format	article
author	Pierre Matricon Anirudh Ranganathan Eugene Warnick Zhan-Guo Gao Axel Rudling Catia Lambertucci Gabriella Marucci Aitakin Ezzati Mariama Jaiteh Diego Dal Ben Kenneth A. Jacobson Jens Carlsson
author_facet	Pierre Matricon Anirudh Ranganathan Eugene Warnick Zhan-Guo Gao Axel Rudling Catia Lambertucci Gabriella Marucci Aitakin Ezzati Mariama Jaiteh Diego Dal Ben Kenneth A. Jacobson Jens Carlsson
author_sort	Pierre Matricon
title	Fragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A 2A adenosine receptor binding site
title_short	Fragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A 2A adenosine receptor binding site
title_full	Fragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A 2A adenosine receptor binding site
title_fullStr	Fragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A 2A adenosine receptor binding site
title_full_unstemmed	Fragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A 2A adenosine receptor binding site
title_sort	fragment optimization for gpcrs by molecular dynamics free energy calculations: probing druggable subpockets of the a 2a adenosine receptor binding site
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/24c1cb3e575e44c6b3e9de6c28191221
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Fragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A 2A adenosine receptor binding site

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