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.
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