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

Current Opinion in Structural Biology
Piero Procacci

Abstract

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.

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Citations

Jun 16, 2021·Expert Opinion on Drug Discovery·AkshatKumar NigamAlán Aspuru-Guzik
Nov 2, 2021·Journal of Chemical Information and Modeling·Marina MacchiagodenaPiero Procacci
Nov 25, 2021·Journal of Chemical Information and Modeling·Zhaoxi SunZhirong Liu

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