Original Paper

Journal of Molecular Modeling

, Volume 14, Issue 2, pp 135-148

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

  • Alexandre BeautraitAffiliated withNancy Université, LORIA, Groupe ORPAILLEUR
  • , Vincent LerouxAffiliated withNancy Université, LORIA, Groupe ORPAILLEUR
  • , Matthieu ChaventAffiliated withNancy Université, LORIA, Groupe ORPAILLEUR
  • , Léo GhemtioAffiliated withNancy Université, LORIA, Groupe ORPAILLEUR
  • , Marie-Dominique DevignesAffiliated withNancy Université, LORIA, Groupe ORPAILLEUR
  • , Malika Smaïl-TabboneAffiliated withNancy Université, LORIA, Groupe ORPAILLEUR
  • , Wensheng CaiAffiliated withDepartment of Chemistry, Nankai University
  • , Xuegang ShaoAffiliated withDepartment of Chemistry, Nankai University
  • , Gilles MoreauAffiliated with
    • , Peter BladonAffiliated withInterprobe Chemical Services
    • , Jianhua YaoAffiliated withLaboratory of Computer Chemistry and Chemoinformatics, Shanghai Institute of Organic Chemistry
    • , Bernard MaigretAffiliated withNancy Université, LORIA, Groupe ORPAILLEUR Email author 

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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.

http://static-content.springer.com/image/art%3A10.1007%2Fs00894-007-0257-9/MediaObjects/894_2007_257_Figa_HTML.gif
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