Alchemical Free Energy Methods Applied to Complexes of the First Bromodomain of BRD4.

ABSTRACT: Accurate and rapid predictions of the binding affinity of a compound to a target are one of the ultimate goals of computer aided drug design. Alchemical approaches to free energy estimations follow the path from an initial state of the system to the final state through alchemical changes of the energy function during a molecular dynamics simulation. Herein, we explore the accuracy and efficiency of two such techniques: relative free energy perturbation (FEP) and multisite lambda dynamics (MSλD). These are applied to a series of inhibitors for the bromodomain-containing protein 4 (BRD4). We demonstrate a procedure for obtaining accurate relative binding free energies using MSλD when dealing with a change in the net charge of the ligand. This resulted in an impressive comparison with experim

SUBMITTER: Guest EE 

PROVIDER: S-EPMC9098113 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature