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

[ Vol. 17 , Issue. 23 ]

Author(s):

Robert Abel, Lingle Wang, David L. Mobley and Richard A. Friesner   Pages 2577 - 2585 ( 9 )

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.

Affiliation:

Schrödinger, Inc., 120 West 45th Street, New York, NY 10036, Schrödinger, Inc., 120 West 45th Street, New York, NY 10036, Departments of Pharmaceutical Sciences and Chemistry, University of California, Irvine, CA 92697, Department of Chemistry, Columbia University, 3000 Broadway, New York, NY 10027

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