Combined Free-Energy Calculation and Machine Learning Methods for Understanding Ligand Unbinding Kinetics.

ABSTRACT: The determination of drug residence times, which define the time an inhibitor is in complex with its target, is a fundamental part of the drug discovery process. Synthesis and experimental measurements of kinetic rate constants are, however, expensive and time consuming. In this work, we aimed to obtain drug residence times computationally. Furthermore, we propose a novel algorithm to identify molecular design objectives based on ligand unbinding kinetics. We designed an enhanced sampling technique to accurately predict the free-energy profiles of the ligand unbinding process, focusing on the free-energy barrier for unbinding. Our method first identifies unbinding paths determining a corresponding set of internal coordinates (ICs) that form contacts between the protein and the ligand; it t

SUBMITTER: Badaoui M 

PROVIDER: S-EPMC9097281 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature