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Substantial improvements in large-scale redocking and screening using the novel HYDE scoring function

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Abstract

The HYDE scoring function consistently describes hydrogen bonding, the hydrophobic effect and desolvation. It relies on HYdration and DEsolvation terms which are calibrated using octanol/water partition coefficients of small molecules. We do not use affinity data for calibration, therefore HYDE is generally applicable to all protein targets. HYDE reflects the Gibbs free energy of binding while only considering the essential interactions of protein–ligand complexes. The greatest benefit of HYDE is that it yields a very intuitive atom-based score, which can be mapped onto the ligand and protein atoms. This allows the direct visualization of the score and consequently facilitates analysis of protein–ligand complexes during the lead optimization process. In this study, we validated our new scoring function by applying it in large-scale docking experiments. We could successfully predict the correct binding mode in 93% of complexes in redocking calculations on the Astex diverse set, while our performance in virtual screening experiments using the DUD dataset showed significant enrichment values with a mean AUC of 0.77 across all protein targets with little or no structural defects. As part of these studies, we also carried out a very detailed analysis of the data that revealed interesting pitfalls, which we highlight here and which should be addressed in future benchmark datasets.

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Acknowledgments

We thank the organizers of the Docking and Scoring Symposium for the arrangement of the very interesting session at the 241st ACS National Meeting. The HYDE project was funded by Bayer CropScience AG and Bayer Pharma AG. We also thank the whole team at the BioSolveIT GmbH for carrying out the elaborate computations for this study.

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Authors and Affiliations

  1. Center for Bioinformatics, University of Hamburg, Bundesstr. 43, 20146, Hamburg, Germany

    Nadine Schneider & Matthias Rarey

  2. BioSolveIT GmbH, An der Ziegelei 79, 53757, St. Augustin, Germany

    Sally Hindle, Holger Claußen, Marcus Gastreich & Christian Lemmen

  3. Bayer CropScience AG, Industriepark Hoechst, G836, 65926, Frankfurt am Main, Germany

    Gudrun Lange, Robert Klein & Jürgen Albrecht

  4. Bayer Pharma AG, Global Drug Discovery, Müllerstr. 178, 13353, Berlin, Germany

    Hans Briem

  5. Bayer Pharma AG, Global Drug Discovery, Aprather Weg 18A, 42113, Wuppertal, Germany

    Kristin Beyer

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  1. Nadine Schneider
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Correspondence to Matthias Rarey.

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Schneider, N., Hindle, S., Lange, G. et al. Substantial improvements in large-scale redocking and screening using the novel HYDE scoring function. J Comput Aided Mol Des 26, 701–723 (2012). https://doi.org/10.1007/s10822-011-9531-0

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