A challenging system: Free energy prediction for factor Xa

Authors

  • Hannes G. Wallnoefer,

    1. Computational Chemistry, Lead Identification and Optimization Support, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach, Germany
    2. Institute of General, Inorganic and Theoretical Chemistry, Faculty of Chemistry and Pharmacy, University of Innsbruck, Innrain 52a, 6020 Innsbruck, Austria
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  • Klaus R. Liedl,

    Corresponding author
    1. Institute of General, Inorganic and Theoretical Chemistry, Faculty of Chemistry and Pharmacy, University of Innsbruck, Innrain 52a, 6020 Innsbruck, Austria
    • Institute of General, Inorganic and Theoretical Chemistry, Faculty of Chemistry and Pharmacy, University of Innsbruck, Innrain 52a, 6020 Innsbruck, Austria
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  • Thomas Fox

    1. Computational Chemistry, Lead Identification and Optimization Support, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach, Germany
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Abstract

Factor Xa (fXa) is a promising target for antithrombotic drugs. Recently, we presented a molecular dynamics study on fXa, which highlighted the need for a careful system setup to obtain stable simulations. Here, we show that these simulations can be used to predict the free energy of binding of several fXa inhibitors. We tested molecular mechanics/Poisson–Boltzmann surface area, molecular mechanics/Generalized Born surface area, and linear interaction energy (LIE) on a small data set of fXa ligands. The continuum solvent approaches only yield satisfying correlations to the experimental results if some of the water molecules are explicitly included in the free energy calculations. LIE gave reasonable results if a sufficiently large data set is used. In general, our procedure of setting up the fXa simulation system enabled MD simulations, which produce adequate ensembles for free energy calculations. © 2011 Wiley Periodicals, Inc. J Comput Chem 2011

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