Journal of Computer-Aided Molecular Design

, Volume 26, Issue 6, pp 701–723 | Cite as

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

  • Nadine Schneider
  • Sally Hindle
  • Gudrun Lange
  • Robert Klein
  • Jürgen Albrecht
  • Hans Briem
  • Kristin Beyer
  • Holger Claußen
  • Marcus Gastreich
  • Christian Lemmen
  • Matthias Rarey
Article

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.

Keywords

Virtual screening Docking Protein–ligand interactions Binding affinity Scoring HYDE 

Supplementary material

10822_2011_9531_MOESM1_ESM.pdf (277 kb)
Supplementary material 1 (PDF 277 kb)

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Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Nadine Schneider
    • 1
  • Sally Hindle
    • 2
  • Gudrun Lange
    • 3
  • Robert Klein
    • 3
  • Jürgen Albrecht
    • 3
  • Hans Briem
    • 4
  • Kristin Beyer
    • 5
  • Holger Claußen
    • 2
  • Marcus Gastreich
    • 2
  • Christian Lemmen
    • 2
  • Matthias Rarey
    • 1
  1. 1.Center for Bioinformatics, University of HamburgHamburgGermany
  2. 2.BioSolveIT GmbHSt. AugustinGermany
  3. 3.Bayer CropScience AGFrankfurt am MainGermany
  4. 4.Bayer Pharma AG, Global Drug DiscoveryBerlinGermany
  5. 5.Bayer Pharma AG, Global Drug DiscoveryWuppertalGermany

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