A Critical Review of Validation, Blind Testing, and Real- World Use of Alchemical Protein-Ligand Binding Free Energy Calculations

Title:A Critical Review of Validation, Blind Testing, and Real- World Use of Alchemical Protein-Ligand Binding Free Energy Calculations

Volume: 17 Issue: 23

Author(s): Robert Abel*, Lingle Wang, David L. Mobley and Richard A. Friesner

Affiliation:

• Schrödinger, Inc., 120 West 45^th Street, New York, NY 10036,United States

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.

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.

Cite this article as:

Abel Robert *, Wang Lingle, Mobley L. David and Friesner A. Richard, A Critical Review of Validation, Blind Testing, and Real- World Use of Alchemical Protein-Ligand Binding Free Energy Calculations, Current Topics in Medicinal Chemistry 2017; 17 (23) . https://dx.doi.org/10.2174/1568026617666170414142131