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A new method for estimating the relative binding free energy, derived from a free energy variational principle for the Pim-1-kinase–ligand and FKBP–ligand systems

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Abstract

In this study, a new method is proposed for calculating the relative binding free energy between a ligand and a protein, derived from a free energy variational principle (FEVP). To address the shortcomings of the method used in our previous study, we incorporate the dynamical fluctuation of a ligand in the FEVP calculation. The present modified method is applied to the Pim-1-kinase–ligand system and also to the FKBP–ligand system as a comparison with our previous work. Any inhibitor of Pim-1 kinase is expected to function as an anti-cancer drug. Some improvements are observed in the results compared to the previous study. The present work also shows comparable or better results than approaches using a standard technique of binding free energy calculations, such as the LIE and the MM-PB/SA methods. The possibility of applying the present method in the drug discovery process is also discussed.

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  1. Department of Bioinformatics, College of Life Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga, 525-8577, Japan

    Takeshi Ashida & Takeshi Kikuchi

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  1. Takeshi Ashida
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Ashida, T., Kikuchi, T. A new method for estimating the relative binding free energy, derived from a free energy variational principle for the Pim-1-kinase–ligand and FKBP–ligand systems. J Comput Aided Mol Des 34, 647–658 (2020). https://doi.org/10.1007/s10822-020-00302-4

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