Impact of Conformational Flexibility on Three-Dimensional Similarity Searching Using Correlation Vectors

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• 作者：Steffen Renner ; Christof H. Schwab ; Johann Gasteiger ; Gisbert Schneider
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2006
• 出版时间：November 2006
• 年：2006
• 卷：46
• 期：6
• 页码：2324 - 2332
• 全文大小：196K
• 年卷期：v.46,no.6(November 2006)
• ISSN：1549-960X

文摘

Many three-dimensional (3D) virtual screening concepts, like automated docking or pharmacophore searching,rely on the calculation of a "bioactive" or "receptor-relevant" conformation of a molecule to assess itsbiological activity. We investigated the dependence of the presence of conformations near the "bioactive"conformation on three-dimensional similarity searching with pharmacophore-based correlation vectors(CATS3D approach). Cocrystal structures of 11 target classes served as queries for virtual screening of adatabase of annotated ligands. Different numbers of conformations were calculated. Single 3D structureswere obtained using the 3D structure generator CORINA and conformational ensembles by the conformationgeneration program ROTATE. This approach was able to reproduce conformations for high resolutioncocrystal structures. For virtual screening we found that using only the CORINA-generated singleconformation already resulted in a significant enrichment of isofunctional molecules having the same biologicalproperty profile. This observation was also made for ligand classes with many rotatable bonds. Althoughmore similar conformations were considered to be more similar in the CATS3D description, the impact ofusing multiple conformations on the enrichment of actives was not as high as expected. CATS3D providesan alignment-free three-dimensional virtual screening approach that is less dependent on the presence ofconformations which are close to the "bioactive" conformation of a molecule compared to methods thatrely on an explicit three-dimensional alignment of molecules.