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Chemical space sampling by different scoring functions and crystal structures

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Abstract

Virtual screening has become a popular tool to identify novel leads in the early phases of drug discovery. A variety of docking and scoring methods used in virtual screening have been the subject of active research in an effort to gauge limitations and articulate best practices. However, how to best utilize different scoring functions and various crystal structures, when available, is not yet well understood. In this work we use multiple crystal structures of PI3 K-γ in both prospective and retrospective virtual screening experiments. Both Glide SP scoring and Prime MM-GBSA rescoring are utilized in the prospective and retrospective virtual screens, and consensus scoring is investigated in the retrospective virtual screening experiments. The results show that each of the different crystal structures that was used, samples a different chemical space, i.e. different chemotypes are prioritized by each structure. In addition, the different (re)scoring functions prioritize different chemotypes as well. Somewhat surprisingly, the Prime MM-GBSA scoring function generally gives lower enrichments than Glide SP. Finally we investigate the impact of different ligand preparation protocols on virtual screening enrichment factors. In summary, different crystal structures and different scoring functions are complementary to each other and allow for a wider variety of chemotypes to be considered for experimental follow-up.

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Acknowledgments

NB thanks Derek Cole and Mike Bowman for support of the VS efforts, Jason Jussif for experimental testing of VS hits, Joel Bard and Kris Svenson for PI3 K-γ crystal structures, and Yongbo Hu for preparation of CORP and CNAV VS libraries.

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  1. Structural Biology and Computational Chemistry, Wyeth Research, 401 N. Middletown Road, Pearl River, NY, USA

    Natasja Brooijmans

  2. Lead Finding Platform, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, USA

    Natasja Brooijmans

  3. Structural Biology and Computational Chemistry, Wyeth Research, CN 8000, Princeton, NJ, USA

    Christine Humblet

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Brooijmans, N., Humblet, C. Chemical space sampling by different scoring functions and crystal structures. J Comput Aided Mol Des 24, 433–447 (2010). https://doi.org/10.1007/s10822-010-9356-2

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