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    Fast and Efficient in Silico 3D Screening:  Toward Maximum Computational Efficiency of Pharmacophore-Based and Shape-Based Approaches
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    Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences (CMBI), University of Innsbruck, Innrain 52, A-6020 Innsbruck, Austria, and Inte:Ligand Software-Entwicklungs- und Consulting GmbH, Clemens Maria Hofbauer-Gasse 6, A-2344 Maria Enzersdorf, Austria
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    Journal of Chemical Information and Modeling

    Cite this: J. Chem. Inf. Model. 2007, 47, 6, 2182–2196
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    https://doi.org/10.1021/ci700024q
    Published October 11, 2007
    Copyright © 2007 American Chemical Society
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    Abstract

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    In continuation of our recent studies on the quality of conformational models generated with CATALYST and OMEGA we present a large-scale survey focusing on the impact of conformational model quality and several screening parameters on pharmacophore-based and shape-based virtual high throughput screening (vHTS). Therefore, we collected known active compounds of CDK2, p38 MAPK, PPAR-γ, and factor Xa and built a set of druglike decoys using ilib:diverse. Subsequently, we generated 3D structures using CORINA and also calculated conformational models for all compounds using CAESAR, CATALYST FAST, and OMEGA. A widespread set of 103 structure-based pharmacophore models was developed with LigandScout for virtual screening with CATALYST. The performance of both database search modes (FAST and BEST flexible database search) as well as the fit value calculation procedures (FAST and BEST fit) available in CATALYST were analyzed in terms of their ability to discriminate between active and inactive compounds and in terms of efficiency. Moreover, these results are put in direct comparison to the performance of the shape-based virtual screening platform ROCS. Our results prove that high enrichment rates are not necessarily in conflict with efficient vHTS settings:  In most of the experiments, we obtained the highest yield of actives in the hit list when parameter sets for the fastest search algorithm were used.

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     University of Innsbruck.

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     Inte:Ligand Software-Entwicklungs- und Consulting GmbH.

    *

     Corresponding author phone:  +43-512-507-5252; fax:  +43-512-507-5269; e-mail:  [email protected].

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    Structural data, physicochemical property distributions, and literature references on the actives and inactives compounds sets, the enrichment factors obtained by different virtual screening setups, and data on Se, Sp, and enrichment factors of ROCS screening. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Cite this: J. Chem. Inf. Model. 2007, 47, 6, 2182–2196
    Click to copy citationCitation copied!
    https://doi.org/10.1021/ci700024q
    Published October 11, 2007
    Copyright © 2007 American Chemical Society
    Request reuse permissions

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