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Best Practices in Free Energy Calculations for Drug Design

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Computational Drug Discovery and Design

Part of the book series: Methods in Molecular Biology ((MIMB,volume 819))

Abstract

Free energy calculations are increasingly of interest for computing biophysical properties of novel small molecules of interest in drug design, such as protein–ligand binding affinities and small molecule partition coefficients. However, these calculations are also notoriously difficult to implement correctly. In this article, we review standard methods for computing free energy differences via simulation, discuss current best practices, and examine potential pitfalls for computational researchers without extensive experience in such calculations. We include a variety of examples and tips for how to set up and conduct these calculations, including applications to relative binding affinities and absolute binding free energies.

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Acknowledgments

The author wishes to thank John Chodera (UC-Berkeley) and David Mobley (University of New Orleans) for ongoing discussions of reliability and usability for free energy calculations.

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  1. Department of Chemical Engineering, University of Virginia, Charlottesville, VA, USA

    Michael R. Shirts

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  1. Michael R. Shirts
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Correspondence to Michael R. Shirts .

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Editors and Affiliations

  1. University of Utah, 30 South 2000 East Rm 307, Salt Lake City, 84112-5820, California, USA

    Riccardo Baron

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Shirts, M.R. (2012). Best Practices in Free Energy Calculations for Drug Design. In: Baron, R. (eds) Computational Drug Discovery and Design. Methods in Molecular Biology, vol 819. Springer, New York, NY. https://doi.org/10.1007/978-1-61779-465-0_26

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  • DOI: https://doi.org/10.1007/978-1-61779-465-0_26

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