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

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

Journal Name: Current Topics in Medicinal Chemistry

Volume 17 , Issue 23 , 2017

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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.

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Article Details

VOLUME: 17
ISSUE: 23
Year: 2017
Page: [2577 - 2585]
Pages: 9
DOI: 10.2174/1568026617666170414142131
Price: $58

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