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Virtual fragment screening: exploration of MM-PBSA re-scoring

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Abstract

An NMR fragment screening dataset with known binders and decoys was used to evaluate the ability of docking and re-scoring methods to identify fragment binders. Re-scoring docked poses using the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) implicit solvent model identifies additional active fragments relative to either docking or random fragment screening alone. Early enrichment, which is clearly most important in practice for selecting relatively small sets of compounds for experimental testing, is improved by MM-PBSA re-scoring. In addition, the value in MM-PBSA re-scoring of docked poses for virtual screening may be in lessening the effect of the variation in the protein complex structure used.

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Acknowledgments

We thank Steve Wesolowski for useful discussions and comments on the manuscript.

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Authors and Affiliations

  1. Infection Innovative Medicines Unit, Chemistry Department, AstraZeneca, R&D Boston, 35 Gatehouse Drive, Waltham, MA, 02451, USA

    Sameer Kawatkar, Demetri Moustakas, Matthew Miller & Diane Joseph-McCarthy

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  1. Sameer Kawatkar
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  2. Demetri Moustakas
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Correspondence to Diane Joseph-McCarthy.

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Kawatkar, S., Moustakas, D., Miller, M. et al. Virtual fragment screening: exploration of MM-PBSA re-scoring. J Comput Aided Mol Des 26, 921–934 (2012). https://doi.org/10.1007/s10822-012-9590-x

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