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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 (...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2020
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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. |
format | Online Article Text |
id | pubmed-7066661 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
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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