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Journal of Molecular Modeling

, Volume 14, Issue 2, pp 135–148 | Cite as

Multiple-step virtual screening using VSM-G: overview and validation of fast geometrical matching enrichment

  • Alexandre Beautrait
  • Vincent Leroux
  • Matthieu Chavent
  • Léo Ghemtio
  • Marie-Dominique Devignes
  • Malika Smaïl-Tabbone
  • Wensheng Cai
  • Xuegang Shao
  • Gilles Moreau
  • Peter Bladon
  • Jianhua Yao
  • Bernard Maigret
Original Paper

Abstract

Numerous methods are available for use as part of a virtual screening strategy but, as yet, no single method is able to guarantee both a level of confidence comparable to experimental screening and a level of computing efficiency that could drastically cut the costs of early phase drug discovery campaigns. Here, we present VSM-G (virtual screening manager for computational grids), a virtual screening platform that combines several structure-based drug design tools. VSM-G aims to be as user-friendly as possible while retaining enough flexibility to accommodate other in silico techniques as they are developed. In order to illustrate VSM-G concepts, we present a proof-of-concept study of a fast geometrical matching method based on spherical harmonics expansions surfaces. This technique is implemented in VSM-G as the first module of a multiple-step sequence tailored for high-throughput experiments. We show that, using this protocol, notable enrichment of the input molecular database can be achieved against a specific target, here the liver-X nuclear receptor. The benefits, limitations and applicability of the VSM-G approach are discussed. Possible improvements of both the geometrical matching technique and its implementation within VSM-G are suggested.

Figure

Basic principle of the virtual screening funnel process.

Keywords

Multiple-step virtual screening VSM-G Structure-based drug design Geometrical matching Spherical harmonics surfaces SHEF GOLD Molecular database enrichment 

Notes

Acknowledgements

We thank Yesmine Asses, Safia Kellou and Amel Maouche for their feedback. Alexandre Beautrait was supported by grants from INRIA (Institut National de Recherche en Informatique et en Automatique), Région Lorraine, and ARC (Association pour la Recherche sur le Cancer); Vincent Leroux by a post-doctoral fellowship from the INCa (Institut National du Cancer); Matthieu Chavent by a joint fellowship between CNRS (Centre National pour la Recherche Scientifique) and Région Lorraine. We thank Openeye for providing free access to OMEGA and VIDA software according to an academic license, Chemaxon for supplying MarvinBeans Java library, CCDC for the trial version of the GOLD program, and the laboratory of chemoinformatics at the Orléans University for the ScreeningAssistant program.

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Alexandre Beautrait
    • 1
  • Vincent Leroux
    • 1
  • Matthieu Chavent
    • 1
  • Léo Ghemtio
    • 1
  • Marie-Dominique Devignes
    • 1
  • Malika Smaïl-Tabbone
    • 1
  • Wensheng Cai
    • 2
  • Xuegang Shao
    • 2
  • Gilles Moreau
    • 3
  • Peter Bladon
    • 4
  • Jianhua Yao
    • 5
  • Bernard Maigret
    • 1
  1. 1.Nancy UniversitéLORIA, Groupe ORPAILLEURVandœuvre-lès-Nancy CedexFrance
  2. 2.Department of ChemistryNankai UniversityTianjinPeople’s Republic of China
  3. 3.CharantonFrance
  4. 4.Interprobe Chemical ServicesGlasgowUK
  5. 5.Laboratory of Computer Chemistry and ChemoinformaticsShanghai Institute of Organic ChemistryShanghaiPeople’s Republic of China

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