Journal Article

Pharmacophore modeling and parallel screening for PPAR ligands

Schuster, Daniela, Markt, Patrick, Kirchmair, Johannes, Laggner, Christian, Langer, Thierry

2007

Overview

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-alpha, PPAR-delta, and PPAR-gamma. 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.

• Publisher: Springer Nature B.V
• Subject: Binding Sites / Computer aided design / Computer Simulation / Databases, Factual / Drug Design / Drug Evaluation, Preclinical / Hypotheses / Ligands / Mathematical models / Models, Molecular / Molecular biology / Peroxisome Proliferator-Activated Receptors - agonists / Peroxisome Proliferator-Activated Receptors - chemistry / Pharmacology / Proteins / Screening / Screens