title: Combining ethnopharmacology and virtual screening for lead structure discovery: COX-inhibitors as application example.
abstract: Virtual screening of large libraries of organic compounds combined with pharmacological high throughput screening is widely used for drug discovery in the pharmaceutical industry. Our aim was to explore the efficiency of using a biased 3D database comprising secondary metabolites from antiinflammatory medicinal plants as a source for the virtual screening. For this study pharmacophore models of cyclooxygenase I and II (COX-1, COX-2), key enzymes in the inflammation process, were generated with structure-based as well as common feature based modeling, resulting in three COX hypotheses. Four different multiconfomational 3D databases limited in molecular weight between 300 and 700 Da were applied to the screening in order to compare and analyze the obtained hit rates. Two of them were created in-house (DIOS, NPD). The database DIOS consists of 2752 compounds from phytochemical reports of antiinflammatory medicinal plants described by the ethnopharmacological source 'De material medica' of Pedanius Dioscorides, whereas NPD contains almost 80,000 compounds gathered arbitrarily from natural sources. In addition, two available multiconformational 3D libraries comprising marketed and development drug substances (DWI and NCI), mainly originating from synthesis, were used for comparison. As a test of the pharmacophore models' capability in natural sources, the models were used to search for known COX inhibitory natural products. This was achieved with some exceptions, which are discussed in the paper. Depending on the hypothesis used, DWI and NCI library searches produced hit rates in the range of 6.6% to 13.7%. A slight increase of the number of molecules assessed for binding was achieved with the database of natural products (NPD). Using the biased 3D database DIOS, however, the average increase of efficiency reached 77% to 133% compared to the hit rates resulting from WDI and NCI. The statistical benefit of a combination of an ethnopharmacological approach with the potential of computer aided drug discovery by in silico screening was demonstrated exemplified on the applied targets COX-1 and COX-2.
authors.affiliation: Institute of Pharmacy, Department of Pharmacognosy, Leopold-Franzens University of Innsbruck, Innrain 52, Josef-Moeller-Haus, A-6020 Innsbruck, Austria. judith.rollinger@uibk.ac.at
authors.forename: Judith M
authors.initials: JM
authors.lastname: Rollinger
authors.forename: Sabine
authors.initials: S
authors.lastname: Haupt
authors.forename: Hermann
authors.initials: H
authors.lastname: Stuppner
authors.forename: Thierry
authors.initials: T
authors.lastname: Langer
mesh_terms: D003198:Computer Simulation; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D030562:Databases, Protein; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D020834:Ethnopharmacology; D007527:Isoenzymes / Q000737:chemistry / Q000187:drug effects; D008419:Materia Medica; D008958:Models, Molecular; D009316:National Institutes of Health (U.S.); D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry / Q000187:drug effects; D011487:Protein Conformation; D014481:United States
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008419:Materia Medica; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases