Predicting ligand binding affinity using on- and off-rates for the SAMPL6 SAMPLing challenge.

Journal of Computer-aided Molecular Design
Tom DixonAlex Dickson

Abstract

Interest in ligand binding kinetics has been growing rapidly, as it is being discovered in more and more systems that ligand residence time is the crucial factor governing drug efficacy. Many enhanced sampling methods have been developed with the goal of predicting ligand binding rates ([Formula: see text]) and/or ligand unbinding rates ([Formula: see text]) through explicit simulation of ligand binding pathways, and these methods work by very different mechanisms. Although there is not yet a blind challenge for ligand binding kinetics, here we take advantage of experimental measurements and rigorously computed benchmarks to compare estimates of [Formula: see text] calculated as the ratio of two rates: [Formula: see text]. These rates were determined using a new enhanced sampling method based on the weighted ensemble framework that we call "REVO": Reweighting of Ensembles by Variance Optimization. This is a further development of the WExplore enhanced sampling method, in which trajectory cloning and merging steps are guided not by the definition of sampling regions, but by maximizing trajectory variance. Here we obtain estimates of [Formula: see text] and [Formula: see text] that are consistent across multiple simulations, with...Continue Reading

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Citations

Jun 11, 2019·Frontiers in Molecular Biosciences·Daria B KokhRebecca C Wade
Jan 28, 2020·Journal of Computer-aided Molecular Design·Andrea RizziJohn D Chodera
Jan 17, 2020·The Journal of Chemical Physics·Hongbin Wan, Vincent A Voelz
Jun 26, 2020·Frontiers in Molecular Biosciences·Robert HallAlex Dickson
Feb 21, 2019·Annual Review of Physical Chemistry·Mattia BernettiAndrea Cavalli
Nov 6, 2020·Journal of Computer-aided Molecular Design·Yiğitcan EkenAngela K Wilson
Nov 14, 2020·Journal of Chemical Information and Modeling·Nurlybek AmangeldiulyMaxim V Fedorov
Sep 30, 2020·Journal of Chemical Theory and Computation·Jeremy Copperman, Daniel M Zuckerman
Dec 1, 2018·Journal of Chemical Information and Modeling·Doris A SchuetzAndrea Cavalli
Apr 22, 2020·Journal of Chemical Information and Modeling·Surl-Hee AhnRommie E Amaro
Aug 22, 2020·Journal of the American Chemical Society·Cristina García-SimónXavi Ribas
Nov 23, 2020·Biophysical Journal·Tom DixonAlex Dickson

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