Abstract

Protein-ligand binding is among the most fundamental phenomena underlying all molecular biology, and a greater ability to more accurately and robustly predict the binding free energy of a small molecule ligand for its cognate protein is expected to have vast consequences for improving the efficiency of pharmaceutical drug discovery. We briefly reviewed a number of scientific and technical advances that have enabled alchemical free energy calculations to recently emerge as a preferred approach, and critically considered proper validation and effective use of these techniques. In particular, we characterized a selection bias effect which may be important in prospective free energy calculations, and introduced a strategy to improve the accuracy of the free energy predictions.

Keywords: Computer-aided drug design, FEP, Free energy, Drug discovery, Structure-based drug discovery, Molecular dynamics, TI, Thermodynamic integration, Alchemical free energy calculations, Protein-ligand binding.

Graphical Abstract