SQUIRRELnovo : de novo design of a PPARalpha 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 s
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 PPARalpha agonist with an EC50 of 44 nM and 100-fold selectivity against PPARgamma 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 PPARalpha with an EC50 of 510 nM.
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Metadaten
Author:Ewgenij Proschak, Kerstin Sander, Heiko Zettl, Yusuf Tanrikulu, Petra Schneider, Oliver Rau, Holger Stark, Manfred Schubert-Zsilavecz, Gisbert Schneider
URN:urn:nbn:de:hebis:30-66676
Document Type:Article
Language:English
Date of Publication (online):2009/06/09
Year of first Publication:2009
Publishing Institution:Univ.-Bibliothek Frankfurt am Main
Release Date:2009/06/09
Note:
© 2009 Weisel et al; licensee BioMed Central Ltd.
Source:Chemistry Central Journal 2009, 3(Suppl 1):O4 ; doi:10.1186/1752-153X-3-S1-O4 ; http://www.journal.chemistrycentral.com/content/3/S1/O4 ;4th German Conference on Chemoinformatics Goslar, Germany. 9–11 November 2008
HeBIS PPN:214267946
Institutes:Biochemie und Chemie
Dewey Decimal Classification:540 Chemie und zugeordnete Wissenschaften
Sammlungen:Universitätspublikationen
Licence (German):License Logo Veröffentlichungsvertrag für Publikationen

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