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SQUIRRELnovo: de novo design of a PPARα agonist by bioisosteric replacement
Chemistry Central Journal volume 3, Article number: O4 (2009)
Shape complementarity is a compulsory condition for molecular recognition . In our 3D ligand-based virtual screening approach called SQUIRREL, we combine shape-based rigid body alignment  with fuzzy pharmacophore scoring . 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  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 . 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  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.
Schneider G, Baringhaus K-H: Molecular Design – Concepts and Applications. 2008, Wiley-VCH: Weinheim, New York
Proschak , et al: J Comput Chem. 2008, 29: 108-10.1002/jcc.20770.
Tanrikulu , et al: Chem Bio Chem. 2007, 8: 1932-
Bron C, Kerbosch J: Communications of the ACM. 1973, 16: 575-577. 10.1145/362342.362367.
Schneider P, Schneider G: QSAR Comb Sci. 2003, 22: 713-718. 10.1002/qsar.200330825.
Sierra , et al: J Med Chem. 2007, 50: 685-10.1021/jm058056x.
Rau , et al: Planta Med. 2006, 72: 881-10.1055/s-2006-946680.
Derksen , et al: Chem Med Chem. 2006, 1: 1346-
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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
- Virtual Screening
- Retrospective Validation
- Virtual Screening Study
- Virtual Screening Approach
- Bioisosteric Replacement