Predicting Binding Free Energies in a Large Combinatorial Chemical Space Using Multisite λ Dynamics

The Journal of Physical Chemistry Letters
Jonah Z VilseckCharles L Brooks

Abstract

In this study, we demonstrate the extensive scalability of the biasing potential replica exchange multisite λ dynamics (BP-REX MSλD) free energy method by calculating binding affinities for 512 inhibitors to HIV Reverse Transcriptase (HIV-RT). This is the largest exploration of chemical space using free energy methods known to date, requires only a few simulations, and identifies 55 new inhibitor designs against HIV-RT predicted to be at least as potent as a tight binding reference compound (i.e., as potent as 56 nM). We highlight that BP-REX MSλD requires an order of magnitude less computational resources than conventional free energy methods while maintaining a similar level of precision, overcomes the inherent poor scalability of conventional free energy methods, and enables the exploration of combinatorially large chemical spaces in the context of in silico drug discovery.

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Citations

Sep 4, 2018·Protein Science : a Publication of the Protein Society·Ryan L HayesCharles L Brooks
Apr 23, 2021·Journal of Chemical Information and Modeling·Lauren NelsonDaniel J Cole
Jun 9, 2021·Journal of Chemical Theory and Computation·Jonah Z VilseckCharles L Brooks
Dec 2, 2019·Chemical Science·Vytautas GapsysBert L de Groot
Nov 18, 2020·Journal of Chemical Theory and Computation·E Prabhu RamanCharles L Brooks
Jun 20, 2020·Journal of Chemical Theory and Computation·Yaozong Li, Kwangho Nam
Mar 2, 2019·Journal of Chemical Theory and Computation·David F Hahn, Philippe H Hünenberger
Aug 19, 2020·Journal of Chemical Information and Modeling·Alexander D Wade, David J Huggins
Aug 7, 2019·The Journal of Physical Chemistry Letters·Jonah Z VilseckCharles L Brooks
Feb 19, 2019·Journal of Chemical Theory and Computation·Laura Pérez-BenitoGary Tresadern
Oct 29, 2021·Journal of Chemical Theory and Computation·Ryan L HayesCharles L Brooks
Jan 22, 2022·Journal of Chemical Information and Modeling·Gary TresadernHelena Geys

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