Predicting Cyclooxygenase Inhibition by Three-Dimensional Pharmacophoric Profiling. Part I: Model Generation, Validation and Applicability in Ethnopharmacology

Daniela Schuster; Birgit Waltenberger; Johannes Kirchmair; Simona Distinto; Patrick Markt; Hermann Stuppner; Judith M Rollinger; Gerhard Wolber

doi:10.1002/minf.200900071

Predicting Cyclooxygenase Inhibition by Three-Dimensional Pharmacophoric Profiling. Part I: Model Generation, Validation and Applicability in Ethnopharmacology

Mol Inform. 2010 Jan 12;29(1-2):75-86. doi: 10.1002/minf.200900071.

Authors

Daniela Schuster¹, Birgit Waltenberger², Johannes Kirchmair³, Simona Distinto³, Patrick Markt³, Hermann Stuppner², Judith M Rollinger², Gerhard Wolber³

Affiliations

¹ Computer-Aided Molecular Design Group, Department of Pharmaceutical Chemistry, University of Innsbruck, Innrain 52c, A-6020 Innsbruck, Austria fax: (+43) 512-507-5269. Daniela.Schuster@uibk.ac.at.
² Institute of Pharmacy/Pharmacognosy, University of Innsbruck, Innrain 52c, A-6020 Innsbruck, Austria.
³ Computer-Aided Molecular Design Group, Department of Pharmaceutical Chemistry, University of Innsbruck, Innrain 52c, A-6020 Innsbruck, Austria fax: (+43) 512-507-5269.

PMID: 27463850
DOI: 10.1002/minf.200900071

Abstract

3D pharmacophore modeling has evolved as an established and state-of-the-art method for performing in-silico predictions of biological activity. Using one single model is limited to single binding modes, while the combination of several models bears a broader application scope. We demonstrate the generation of a complete and predictive 3D model set for cyclooxygenase 1 and 2 inhibitors, along with a selection and validation protocol optimized for parallel virtual screening. This model set was applied to explain the cyclooxygenase activity of an ethnopharmacologically known mixture of natural products, the Thai traditional medicine "Prasaplai". Results show that rationalizing natural product activity by modern in-silico approaches is promising and can be tremendously useful in the identification of the mechanisms of action for known biological effects of complex herbal remedies.

Keywords: Cyclooxygenase inhibitors; Ethnopharmacology; Medicinal chemistry; Molecular modeling; Parallel screening; Prasaplai.