Discovery of new nanomolar peroxisome proliferator-activated receptor gamma activators via elaborate ligand-based modeling.

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Al-Najjar BO, Wahab HA, Tengku Muhammad TS, Shu-Chien AC, Ahmad Noruddin NA, Taha MO

Discovery of new nanomolar peroxisome proliferator-activated receptor gamma activators via elaborate ligand-based modeling.

Eur J Med Chem. 2011 Jun;46(6):2513-29. doi: 10.1016/j.ejmech.2011.03.040. Epub 2011 Mar 25.

PubMed ID

21482446 [ View in PubMed

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Abstract

Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) activators have drawn great recent attention in the clinical management of type 2 diabetes mellitus, prompting several attempts to discover and optimize new PPARgamma activators. With this in mind, we explored the pharmacophoric space of PPARgamma 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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Rosiglitazone	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	10	N/A	N/A	Details
Rosiglitazone	Peroxisome proliferator-activated receptor gamma	IC 50 (nM)	210	N/A	N/A	Details