title: Identification of novel peroxisome proliferator-activated receptor-gamma (PPARγ) agonists using molecular modeling method.
abstract: Peroxisome proliferator-activated receptor-gamma (PPARγ) plays a critical role in lipid and glucose homeostasis. It is the target of many drug discovery studies, because of its role in various disease states including diabetes and cancer. Thiazolidinediones, a synthetic class of agents that work by activation of PPARγ, have been used extensively as insulin-sensitizers for the management of type 2 diabetes. In this study, a combination of QSAR and docking methods were utilised to perform virtual screening of more than 25 million compounds in the ZINC library. The QSAR model was developed using 1,517 compounds and it identified 42,378 potential PPARγ agonists from the ZINC library, and 10,000 of these were selected for docking with PPARγ based on their diversity. Several steps were used to refine the docking results, and finally 30 potentially highly active ligands were identified. Four compounds were subsequently tested for their in vitro activity, and one compound was found to have a K i values of <5 μM.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore.
authors.forename: Veronica M W
authors.initials: VM
authors.lastname: Gee
authors.forename: Fiona S L
authors.initials: FS
authors.lastname: Wong
authors.forename: Lalitha
authors.initials: L
authors.lastname: Ramachandran
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
authors.forename: Alan Prem
authors.initials: AP
authors.lastname: Kumar
authors.forename: Chun Wei
authors.initials: CW
authors.lastname: Yap
mesh_terms: D001665:Binding Sites; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000473:pathology; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D047495:PPAR gamma / Q000819:agonists* / Q000737:chemistry; D047492:Peroxisome Proliferator-Activated Receptors / Q000737:chemistry; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D045162:Thiazolidinediones / Q000008:administration & dosage*
chemical_list: D008024:Ligands; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D045162:Thiazolidinediones