Journal of Computer-Aided Molecular Design

, Volume 20, Issue 12, pp 717–734 | Cite as

Ultrafast de novo docking combining pharmacophores and combinatorics

  • Marcus Gastreich
  • Markus Lilienthal
  • Hans Briem
  • Holger Claussen
Original paper


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 FlexX C and FlexX-Pharm has been established. The background is explained, and the crucial points from an information scientist’s perspective are highlighted.


Combinatorial chemistry Docking FlexX Pharmacophore vHTS Virtual screening 



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.

Supplementary material

10822_2006_9091_MOESM1_ESM.pdf (79 kb)


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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Marcus Gastreich
    • 1
  • Markus Lilienthal
    • 1
  • Hans Briem
    • 2
  • Holger Claussen
    • 1
  1. 1.BioSolveIT GmbHSt. AugustinGermany
  2. 2.CDCC/Computational ChemistrySchering AGBerlinGermany

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