Volume 3 Supplement 1

4th German Conference on Chemoinformatics: 22. CIC-Workshop

Open Access

SQUIRRELnovo: de novo design of a PPARα agonist by bioisosteric replacement

  • E Proschak1,
  • K Sander1,
  • H Zettl1,
  • Y Tanrikulu1,
  • P Schneider1,
  • O Rau1,
  • H Stark1,
  • M Schubert-Zsilavecz1 and
  • G Schneider1
Chemistry Central Journal20093(Suppl 1):O4

DOI: 10.1186/1752-153X-3-S1-O4

Published: 05 June 2009

Shape complementarity is a compulsory condition for molecular recognition [1]. In our 3D ligand-based virtual screening approach called SQUIRREL, we combine shape-based rigid body alignment [2] with fuzzy pharmacophore scoring [3]. Retrospective validation studies demonstrate the superiority of methods which combine both shape and pharmacophore information on the family of peroxisome proliferator-activated receptors (PPARs). We demonstrate the real-life applicability of SQUIRREL by a prospective virtual screening study, where a potent PPARα agonist with an EC50 of 44 nM and 100-fold selectivity against PPARγ has been identified.

SQUIRREL molecular superposition is based on a graph-matching routine [4] and allows partial matching. We used this advantage for searching for bioisosteric replacement suggestions in a database of molecular fragments derived from a collection of drug-like compounds [5]. The bioisosteric groups suggested by our tool SQURRELnovo, can be used for ligand-based de novo design by a human expert. Using the fibrate derivative GW590735 [6] as query, we designed a novel lead structure by substitution of the acidic head group and hydrophobic tail. The synthesis and following testing in a cell-based reporter gene assay [7, 8] revealed that the designed structure activates PPARα with an EC50 of 510 nM.

Authors’ Affiliations

(1)
Goethe-University Frankfurt am Main

References

  1. Schneider G, Baringhaus K-H: Molecular Design – Concepts and Applications. 2008, Wiley-VCH: Weinheim, New YorkGoogle Scholar
  2. Proschak , et al: J Comput Chem. 2008, 29: 108-10.1002/jcc.20770.View ArticleGoogle Scholar
  3. Tanrikulu , et al: Chem Bio Chem. 2007, 8: 1932-View ArticleGoogle Scholar
  4. Bron C, Kerbosch J: Communications of the ACM. 1973, 16: 575-577. 10.1145/362342.362367.View ArticleGoogle Scholar
  5. Schneider P, Schneider G: QSAR Comb Sci. 2003, 22: 713-718. 10.1002/qsar.200330825.View ArticleGoogle Scholar
  6. Sierra , et al: J Med Chem. 2007, 50: 685-10.1021/jm058056x.View ArticleGoogle Scholar
  7. Rau , et al: Planta Med. 2006, 72: 881-10.1055/s-2006-946680.View ArticleGoogle Scholar
  8. Derksen , et al: Chem Med Chem. 2006, 1: 1346-View ArticleGoogle Scholar

Copyright

© Proschak et al; licensee BioMed Central Ltd. 2009

This article is published under license to BioMed Central Ltd.