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Ultrafast de novo docking combining pharmacophores and combinatorics

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Abstract

We report on a successful de novo design approach which relies on the combination of multi-million compound combinatorial docking under receptor-based pharmacophore constraints. Inspired by a rationale by A.R. Leach et al., we document on the unification of two steps into one for ligand assembly. In the original work, fragments known to bind in protein active sites were connected forming novel ligand compounds by means of generic skeleton linkers and following a combinatorial approach. In our approach, the knowledge of fragments binding to the protein has been expressed in terms of a receptor-based pharmacophore definition. The combinatorial linking step is performed in situ during docking, starting from combinatorial libraries. Three sample scenarios growing in size and complexity (combinatorial libraries of 1 million, 1.3 million, and 22.4 million compounds) have been created to illustrate the method. Docking could be accomplished between minutes and several hours depending on the outset; the results were throughout promising. Technically, a module compatibility between FlexXC and FlexX-Pharm has been established. The background is explained, and the crucial points from an information scientist’s perspective are highlighted.

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Notes

  1. Another, slightly different approach is pursued by Degen and Rarey [23] in their program FlexNovo; the authors employ fragment spaces generated in a chemically sensible way as input to a FlexX-based docking machinery.

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Acknowledgments

We gratefully appreciate comments and hints from Hugo Kubinyi. Thanks also to Robert Klein (Bayer CropScience in Frankfurt, Germany) who helped us during our correlation investigations. We extend our gratitude to Birte Seebeck at University of Hamburg for compiling combinatorial libraries. This work has been partly funded by Schering AG, Berlin, Germany.

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Authors and Affiliations

  1. BioSolveIT GmbH, An der Ziegelei 75, 53757, St. Augustin, Germany

    Marcus Gastreich, Markus Lilienthal & Holger Claussen

  2. CDCC/Computational Chemistry, Schering AG, 13342, Berlin, Germany

    Hans Briem

Authors
  1. Marcus Gastreich
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  2. Markus Lilienthal
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  4. Holger Claussen
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Correspondence to Marcus Gastreich.

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Gastreich, M., Lilienthal, M., Briem, H. et al. Ultrafast de novo docking combining pharmacophores and combinatorics. J Comput Aided Mol Des 20, 717–734 (2006). https://doi.org/10.1007/s10822-006-9091-x

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