Pharmacophore modeling and parallel screening for PPAR ligands
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We describe the generation and validation of pharmacophore models for PPARs, as well as a large scale validation of the parallel screening approach by screening PPAR ligands against a large database of structure-based models. A large test set of 357 PPAR ligands was screened against 48 PPAR models to determine the best models for agonists of PPAR-α, PPAR-δ, and PPAR-γ. Afterwards, a parallel screen was performed using the 357 PPAR ligands and 47 structure-based models for PPARs, which were integrated into a 1537 models comprising in-house pharmacophore database, to assess the enrichment of PPAR ligands within the PPAR hypotheses. For these purposes, we categorized the 1537 database models into 181 protein targets and developed a score that ranks the retrieved targets for each ligand. Thus, we tried to find out if the concept of parallel screening is able to predict the correct pharmacological target for a set of compounds. The PPAR target was ranked first more often than any other target. This confirms the ability of parallel screening to forecast the pharmacological active target for a set of compounds.
KeywordsPPAR LigandScout ilib:diverse Virtual screening Parallel screening Pharmacophore modelling Activity profiling Target fishing
We thank Dr. Rémy D. Hoffmann, Accelrys SARL Paris, for screening the Derwent WDI database.
- 17.Pipeline Pilot, 22.214.171.124. Scitegic, 10188 Telesis Court., Suite 100, San Diego, CA 92121, USAGoogle Scholar
- 18.Catalyst, Version 4.11. Accelrys, 9685 Scranton Road, San Diego, CA 92121, USAGoogle Scholar
- 20.Derwent World Drug Index 2003. Scientific, T., 3501 Market Street, Philadelphia, PA 19104, USAGoogle Scholar
- 21.ilib:diverse, 1.0.2. Inte:Ligand, Clemens Maria Hofbauer-G. 6, A-2344 Maria Enzersdorf, AustriaGoogle Scholar
- 26.Clement OO, Mehl AT (2000) International University Line: La Jolla 71Google Scholar
- 44.Henke BR, Blanchard SG, Brackeen MF, Brown KK, Cobb JE, Collins JL, Harrington WWJ, Hashim MA, Hull-Ryde EA, Kaldor I, Kliewer SA, Lake DH, Leesnitzer LM, Lehmann JM, Lenhard JM, Orband-Miller LA, Miller JF, Mook RAJ, Noble SA, Oliver WJ, Parks DJ, Plunket KD, Szewczyk JR, Willson TM (1998) J Med Chem 41:5020CrossRefGoogle Scholar