Skip to main content
  • Oral presentation
  • Open access
  • Published:

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

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.

References

  1. Schneider G, Baringhaus K-H: Molecular Design – Concepts and Applications. 2008, Wiley-VCH: Weinheim, New York

    Google Scholar 

  2. Proschak , et al: J Comput Chem. 2008, 29: 108-10.1002/jcc.20770.

    Article  CAS  Google Scholar 

  3. Tanrikulu , et al: Chem Bio Chem. 2007, 8: 1932-

    Article  CAS  Google Scholar 

  4. Bron C, Kerbosch J: Communications of the ACM. 1973, 16: 575-577. 10.1145/362342.362367.

    Article  Google Scholar 

  5. Schneider P, Schneider G: QSAR Comb Sci. 2003, 22: 713-718. 10.1002/qsar.200330825.

    Article  CAS  Google Scholar 

  6. Sierra , et al: J Med Chem. 2007, 50: 685-10.1021/jm058056x.

    Article  CAS  Google Scholar 

  7. Rau , et al: Planta Med. 2006, 72: 881-10.1055/s-2006-946680.

    Article  CAS  Google Scholar 

  8. Derksen , et al: Chem Med Chem. 2006, 1: 1346-

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

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

Reprints and permissions

About this article

Cite this article

Proschak, E., Sander, K., Zettl, H. et al. SQUIRRELnovo: de novo design of a PPARα agonist by bioisosteric replacement. Chemistry Central Journal 3 (Suppl 1), O4 (2009). https://doi.org/10.1186/1752-153X-3-S1-O4

Download citation

  • Published:

  • DOI: https://doi.org/10.1186/1752-153X-3-S1-O4

Keywords