Journal of Computer-Aided Molecular Design

, Volume 27, Issue 3, pp 221–234 | Cite as

Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments

  • G. Madhavi Sastry
  • Matvey Adzhigirey
  • Tyler Day
  • Ramakrishna Annabhimoju
  • Woody Sherman
Article

Abstract

Structure-based virtual screening plays an important role in drug discovery and complements other screening approaches. In general, protein crystal structures are prepared prior to docking in order to add hydrogen atoms, optimize hydrogen bonds, remove atomic clashes, and perform other operations that are not part of the x-ray crystal structure refinement process. In addition, ligands must be prepared to create 3-dimensional geometries, assign proper bond orders, and generate accessible tautomer and ionization states prior to virtual screening. While the prerequisite for proper system preparation is generally accepted in the field, an extensive study of the preparation steps and their effect on virtual screening enrichments has not been performed. In this work, we systematically explore each of the steps involved in preparing a system for virtual screening. We first explore a large number of parameters using the Glide validation set of 36 crystal structures and 1,000 decoys. We then apply a subset of protocols to the DUD database. We show that database enrichment is improved with proper preparation and that neglecting certain steps of the preparation process produces a systematic degradation in enrichments, which can be large for some targets. We provide examples illustrating the structural changes introduced by the preparation that impact database enrichment. While the work presented here was performed with the Protein Preparation Wizard and Glide, the insights and guidance are expected to be generalizable to structure-based virtual screening with other docking methods.

Keywords

Virtual screening Protein preparation Protein preparation wizard PrepWizard Docking Enrichment Ligand preparation Epik 

Supplementary material

10822_2013_9644_MOESM1_ESM.xls (86 kb)
Supplementary material 1 (XLS 86 kb)

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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • G. Madhavi Sastry
    • 1
  • Matvey Adzhigirey
    • 2
  • Tyler Day
    • 2
  • Ramakrishna Annabhimoju
    • 1
  • Woody Sherman
    • 2
  1. 1.SchrödingerHyderabadIndia
  2. 2.SchrödingerNew YorkUSA

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