Volume 4 Supplement 1

7th German Conference on Chemoinformatics: 25 CIC-Workshop

Open Access

Fragment-based identification of multi-target ligands by self-organizing map alignment

  • Janosch Achenbach1,
  • Franca-Maria Klingler1,
  • Steffen Hahn1,
  • Svenja Steinbrink1,
  • Mirjam Schroeder1,
  • Frank Loehr1,
  • Volker Doetsch1,
  • Dieter Steinhilber1 and
  • Ewgenij Proschak1
Journal of Cheminformatics20124(Suppl 1):P57


Published: 1 May 2012

In the recent years the prevalent paradigm in drug discovery of „one drug – one target – one disease“, following the assumption that highly selective ligands would avoid unwandted side effects caused by binding to seconday non-theratpeutic targets, got reconsidered. The results of post-genomic and network biology showed that proteins rarely act in isolated systems but rather as a part of a highly connected network [1]. It was further shown that the efficacy of several approved drugs is traced back to the fact that they act on multiple targets [2]. Therefore inhibiting a single target of such a network might not lead to the desired therapeutic effect. These findings lead to a shift towards polypharmacology [3] and the rational design of selective multi-target drugs, which have often improved efficacy [4]. But the design of multi target drugs is still a great challenge in regard of a sufficient activity on each target as well as an adequate pharmacokinetic profile [5]. Early design strategies tried to link the pharmacophors of known inhibitors, however these methods often lead to high molecular weight and low ligand efficiency.

We present a new approach based on self-organizing maps [3, 6] (SOM) for the identification of multi-target fragments. We describe a workflow that initially identifies multi-target relevant substructures with a combination of maximum common substructure search and the alignment of multiple SOMs. Furthermore, these substructures are trained together with a fragment library on additional SOMs to find new multi-target fragments, validated by saturation transfer difference (STD)-NMR and biochemical assay systems. We used our approach for the identification of new dual-acting inhibitors of 5-Lipoxygenase (5-LO) and soluble Epoxide Hydrolase (sEH), both enzymes located in the arachidonic acid cascade and involved in inflammatory processes, pain and cadiovascular diseases.

Authors’ Affiliations

Institute of Pharmaceutical Chemistry, LiFF/OSF/ZAFES, Goethe University, Frankfurt am Main, Germany, Frankfurt/M, Germany


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© Achenbach et al; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.