Protein-ligand binding free energy and kinetics

Predicting drug efficacy with computational tools remains one of the major challenges in drug discovery. Drug efficacy depends on the affinity of a small molecule for its biological counterpart. In addition, it has recently been reported that drug efficacy can also be related to the time that a small molecule spends in contact with its biological target (i.e. the kinetics of unbinding, koff). From a computational standpoint, several approaches to the free energy estimation have been reported, while only a few examples have appeared in the literature aimed at predicting the koff of binary complexes. In this presentation, applications of molecular dynamics (MD) and enhanced sampling approaches (e.g., steered-MD, metadynamics, umbrella sampling, etc.) to estimating protein-ligand binding free energy and kinetics will be discussed.