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

作者：Abel Robert^*; Wang Lingle; Mobley David L; Friesner Richard A

来源：Current Topics in Medicinal Chemistry, 2017, 17(23): 2577-2585.

DOI：10.2174/1568026617666170414142131

• 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

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.

• 出版日期2017