Automation of absolute protein-ligand binding free energy calculations for docking refinement and compound evaluation

Abstract Absolute binding free energy calculations with explicit solvent molecular simulations can provide estimates of protein-ligand affinities, and thus reduce the time and costs needed to find new drug candidates. However, these calculations can be complex to implement and perform. Here, we intr...

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Autores principales:	Germano Heinzelmann, Michael K. Gilson
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a364c3436369474ba4dc7d8ed0d515fb
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spelling	oai:doaj.org-article:a364c3436369474ba4dc7d8ed0d515fb2021-12-02T15:23:00ZAutomation of absolute protein-ligand binding free energy calculations for docking refinement and compound evaluation10.1038/s41598-020-80769-12045-2322https://doaj.org/article/a364c3436369474ba4dc7d8ed0d515fb2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-80769-1https://doaj.org/toc/2045-2322Abstract Absolute binding free energy calculations with explicit solvent molecular simulations can provide estimates of protein-ligand affinities, and thus reduce the time and costs needed to find new drug candidates. However, these calculations can be complex to implement and perform. Here, we introduce the software BAT.py, a Python tool that invokes the AMBER simulation package to automate the calculation of binding free energies for a protein with a series of ligands. The software supports the attach-pull-release (APR) and double decoupling (DD) binding free energy methods, as well as the simultaneous decoupling-recoupling (SDR) method, a variant of double decoupling that avoids numerical artifacts associated with charged ligands. We report encouraging initial test applications of this software both to re-rank docked poses and to estimate overall binding free energies. We also show that it is practical to carry out these calculations cheaply by using graphical processing units in common machines that can be built for this purpose. The combination of automation and low cost positions this procedure to be applied in a relatively high-throughput mode and thus stands to enable new applications in early-stage drug discovery.Germano HeinzelmannMichael K. GilsonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Germano Heinzelmann Michael K. Gilson Automation of absolute protein-ligand binding free energy calculations for docking refinement and compound evaluation
description	Abstract Absolute binding free energy calculations with explicit solvent molecular simulations can provide estimates of protein-ligand affinities, and thus reduce the time and costs needed to find new drug candidates. However, these calculations can be complex to implement and perform. Here, we introduce the software BAT.py, a Python tool that invokes the AMBER simulation package to automate the calculation of binding free energies for a protein with a series of ligands. The software supports the attach-pull-release (APR) and double decoupling (DD) binding free energy methods, as well as the simultaneous decoupling-recoupling (SDR) method, a variant of double decoupling that avoids numerical artifacts associated with charged ligands. We report encouraging initial test applications of this software both to re-rank docked poses and to estimate overall binding free energies. We also show that it is practical to carry out these calculations cheaply by using graphical processing units in common machines that can be built for this purpose. The combination of automation and low cost positions this procedure to be applied in a relatively high-throughput mode and thus stands to enable new applications in early-stage drug discovery.
format	article
author	Germano Heinzelmann Michael K. Gilson
author_facet	Germano Heinzelmann Michael K. Gilson
author_sort	Germano Heinzelmann
title	Automation of absolute protein-ligand binding free energy calculations for docking refinement and compound evaluation
title_short	Automation of absolute protein-ligand binding free energy calculations for docking refinement and compound evaluation
title_full	Automation of absolute protein-ligand binding free energy calculations for docking refinement and compound evaluation
title_fullStr	Automation of absolute protein-ligand binding free energy calculations for docking refinement and compound evaluation
title_full_unstemmed	Automation of absolute protein-ligand binding free energy calculations for docking refinement and compound evaluation
title_sort	automation of absolute protein-ligand binding free energy calculations for docking refinement and compound evaluation
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/a364c3436369474ba4dc7d8ed0d515fb
work_keys_str_mv	AT germanoheinzelmann automationofabsoluteproteinligandbindingfreeenergycalculationsfordockingrefinementandcompoundevaluation AT michaelkgilson automationofabsoluteproteinligandbindingfreeenergycalculationsfordockingrefinementandcompoundevaluation
_version_	1718387344478830592

Automation of absolute protein-ligand binding free energy calculations for docking refinement and compound evaluation

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