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Comparison of Equilibrium and Nonequilibrium Approaches for Relative Binding Free Energy Predictions by Shunzhou Wan; Agastya P. Bhati; Peter V. Coveney is a Physics and Astronomy article available to read on EtoBox.

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Alchemical relative binding free energy calculations have recently found important applications in drug optimization. A series of congeneric compounds are generated from a preidentified lead compound, and their relative binding affinities to a protein are assessed in order to optimize candidate drugs. While methods based on equilibrium thermodynamics have been extensively studied, an approach based on nonequilibrium methods has recently been reported together with claims of its superiority. However, these claims pay insufficient attention to the basis and reliability of both methods. Here we report a comparative study of the two approaches across a large data set, comprising more than 500 ligand transformations spanning in excess of 300 ligands binding to a set of 14 diverse protein targets. Ensemble methods are essential to quantify the uncertainty in these calculations, not only for the reasons already established in the equilibrium approach but also to ensure that the nonequilibrium calculations reside within their domain of validity. If and only if ensemble methods are applied, we find that the nonequilibrium method can achieve accuracy and precision comparable to those of the

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Author

Shunzhou Wan; Agastya P. Bhati; Peter V. Coveney

Publisher

American Chemical Society (ACS)

Published

2023

Language

EN

Field

Physics and Astronomy (Physical Sciences)