Accelerating Alchemical Free Energy Prediction Using a Multistate Method: Application to Multiple Kinases.

ABSTRACT: Alchemical free-energy methods based on molecular dynamics (MD) simulations have become important tools to identify modifications of small organic molecules that improve their protein binding affinity during lead optimization. The routine application of pairwise free-energy methods to rank potential binders from best to worst is impacted by the combinatorial increase in calculations to perform when the number of molecules to assess grows. To address this fundamental limitation, our group has developed replica-exchange enveloping distribution sampling (RE-EDS), a pathway-independent multistate method, enabling the calculation of alchemical free-energy differences between multiple ligands (N > 2) from a single MD simulation. In this work, we apply the method to a set of four kinases w

SUBMITTER: Champion C 

PROVIDER: S-EPMC10685456 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature