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

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 explora

SUBMITTER: Vilseck JZ 

PROVIDER: S-EPMC6091208 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature