Methodological uncertainties in drug-receptor binding free energy predictions based on classical molecular dynamics.

Computational approaches are becoming an essential tool in modern drug design and discovery, with fast compound triaging using a combination of machine learning and docking techniques followed by molecular dynamics binding free energies assessment using alchemical techniques. The traditional MD-based alchemical free energy perturbation (FEP) method faces severe sampling issues that may limits its reliability in automated workflows. Here we review the major sources of uncertainty in FEP protocols for drug discovery, showing how the sampling problem can be effectively tackled by switching to nonequilibrium alchemical techniques.