title: Discovery of new nanomolar peroxisome proliferator-activated receptor γ activators via elaborate ligand-based modeling.
abstract: Peroxisome Proliferator-Activated Receptor γ (PPARγ) activators have drawn great recent attention in the clinical management of type 2 diabetes mellitus, prompting several attempts to discover and optimize new PPARγ activators. With this in mind, we explored the pharmacophoric space of PPARγ using seven diverse sets of activators. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of accessing self-consistent and predictive quantitative structure-activity relationship (QSAR) (r2(71)=0.80, F=270.3, r2LOO=0.73, r2PRESS against 17 external test inhibitors=0.67). Three orthogonal pharmacophores emerged in the QSAR equation and were validated by receiver operating characteristic (ROC) curves analysis. The models were then used to screen the national cancer institute (NCI) list of compounds. The highest-ranking hits were tested in vitro. The most potent hits illustrated EC50 values of 15 and 224 nM.
authors.affiliation: Pharmaceutical Design and Simulation (PhDS) Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Minden, Pulau Pinang, Malaysia.
authors.forename: Belal O
authors.initials: BO
authors.lastname: Al-Najjar
authors.forename: Habibah A
authors.initials: HA
authors.lastname: Wahab
authors.forename: Tengku Sifzizul
authors.initials: TS
authors.lastname: Tengku Muhammad
authors.forename: Alexander Chong
authors.initials: AC
authors.lastname: Shu-Chien
authors.forename: Nur Adelina
authors.initials: NA
authors.lastname: Ahmad Noruddin
authors.forename: Mutasem O
authors.initials: MO
authors.lastname: Taha
mesh_terms: D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D056945:Hep G2 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D012372:ROC Curve; D013237:Stereoisomerism
chemical_list: D008024:Ligands; D047495:PPAR gamma