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Fast, Accurate, and Reliable Protocols for Routine Calculations of Protein–Ligand Binding Affinities in Drug Design Projects Using AMBER GPU-TI with ff14SB/GAFF

[Image: see text] Accurate prediction of the absolute or relative protein–ligand binding affinity is one of the major tasks in computer-aided drug design projects, especially in the stage of lead optimization. In principle, the alchemical free energy (AFE) methods such as thermodynamic integration (...

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Autores principales: He, Xibing, Liu, Shuhan, Lee, Tai-Sung, Ji, Beihong, Man, Viet H., York, Darrin M., Wang, Junmei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2020
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066661/
https://www.ncbi.nlm.nih.gov/pubmed/32175507
http://dx.doi.org/10.1021/acsomega.9b04233
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author He, Xibing
Liu, Shuhan
Lee, Tai-Sung
Ji, Beihong
Man, Viet H.
York, Darrin M.
Wang, Junmei
author_facet He, Xibing
Liu, Shuhan
Lee, Tai-Sung
Ji, Beihong
Man, Viet H.
York, Darrin M.
Wang, Junmei
author_sort He, Xibing
collection PubMed
description [Image: see text] Accurate prediction of the absolute or relative protein–ligand binding affinity is one of the major tasks in computer-aided drug design projects, especially in the stage of lead optimization. In principle, the alchemical free energy (AFE) methods such as thermodynamic integration (TI) or free-energy perturbation (FEP) can fulfill this task, but in practice, a lot of hurdles prevent them from being routinely applied in daily drug design projects, such as the demanding computing resources, slow computing processes, unavailable or inaccurate force field parameters, and difficult and unfriendly setting up and post-analysis procedures. In this study, we have exploited practical protocols of applying the CPU (central processing unit)-TI and newly developed GPU (graphic processing unit)-TI modules and other tools in the AMBER software package, combined with ff14SB/GAFF1.8 force fields, to conduct efficient and accurate AFE calculations on protein–ligand binding free energies. We have tested 134 protein–ligand complexes in total for four target proteins (BACE, CDK2, MCL1, and PTP1B) and obtained overall comparable performance with the commercial Schrodinger FEP+ program ( WangJ. Am. Chem. Soc.2015, 137, 2695−270325625324). The achieved accuracy fits within the requirements for computations to generate effective guidance for experimental work in drug lead optimization, and the needed wall time is short enough for practical application. Our verified protocol provides a practical solution for routine AFE calculations in real drug design projects.
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spelling pubmed-70666612020-03-13 Fast, Accurate, and Reliable Protocols for Routine Calculations of Protein–Ligand Binding Affinities in Drug Design Projects Using AMBER GPU-TI with ff14SB/GAFF He, Xibing Liu, Shuhan Lee, Tai-Sung Ji, Beihong Man, Viet H. York, Darrin M. Wang, Junmei ACS Omega [Image: see text] Accurate prediction of the absolute or relative protein–ligand binding affinity is one of the major tasks in computer-aided drug design projects, especially in the stage of lead optimization. In principle, the alchemical free energy (AFE) methods such as thermodynamic integration (TI) or free-energy perturbation (FEP) can fulfill this task, but in practice, a lot of hurdles prevent them from being routinely applied in daily drug design projects, such as the demanding computing resources, slow computing processes, unavailable or inaccurate force field parameters, and difficult and unfriendly setting up and post-analysis procedures. In this study, we have exploited practical protocols of applying the CPU (central processing unit)-TI and newly developed GPU (graphic processing unit)-TI modules and other tools in the AMBER software package, combined with ff14SB/GAFF1.8 force fields, to conduct efficient and accurate AFE calculations on protein–ligand binding free energies. We have tested 134 protein–ligand complexes in total for four target proteins (BACE, CDK2, MCL1, and PTP1B) and obtained overall comparable performance with the commercial Schrodinger FEP+ program ( WangJ. Am. Chem. Soc.2015, 137, 2695−270325625324). The achieved accuracy fits within the requirements for computations to generate effective guidance for experimental work in drug lead optimization, and the needed wall time is short enough for practical application. Our verified protocol provides a practical solution for routine AFE calculations in real drug design projects. American Chemical Society 2020-02-25 /pmc/articles/PMC7066661/ /pubmed/32175507 http://dx.doi.org/10.1021/acsomega.9b04233 Text en Copyright © 2020 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle He, Xibing
Liu, Shuhan
Lee, Tai-Sung
Ji, Beihong
Man, Viet H.
York, Darrin M.
Wang, Junmei
Fast, Accurate, and Reliable Protocols for Routine Calculations of Protein–Ligand Binding Affinities in Drug Design Projects Using AMBER GPU-TI with ff14SB/GAFF
title Fast, Accurate, and Reliable Protocols for Routine Calculations of Protein–Ligand Binding Affinities in Drug Design Projects Using AMBER GPU-TI with ff14SB/GAFF
title_full Fast, Accurate, and Reliable Protocols for Routine Calculations of Protein–Ligand Binding Affinities in Drug Design Projects Using AMBER GPU-TI with ff14SB/GAFF
title_fullStr Fast, Accurate, and Reliable Protocols for Routine Calculations of Protein–Ligand Binding Affinities in Drug Design Projects Using AMBER GPU-TI with ff14SB/GAFF
title_full_unstemmed Fast, Accurate, and Reliable Protocols for Routine Calculations of Protein–Ligand Binding Affinities in Drug Design Projects Using AMBER GPU-TI with ff14SB/GAFF
title_short Fast, Accurate, and Reliable Protocols for Routine Calculations of Protein–Ligand Binding Affinities in Drug Design Projects Using AMBER GPU-TI with ff14SB/GAFF
title_sort fast, accurate, and reliable protocols for routine calculations of protein–ligand binding affinities in drug design projects using amber gpu-ti with ff14sb/gaff
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066661/
https://www.ncbi.nlm.nih.gov/pubmed/32175507
http://dx.doi.org/10.1021/acsomega.9b04233
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