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

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• 作者：Belal O. Al-Najjar ; Habibah A. Wahab ; Tengku Sifzizul Tengku Muhammad ; Alex ; er Chong Shu-Chien ; Nur Adelina Ahmad Noruddin ; Mutasem O. Taha
• 关键词：Peroxisome Proliferator-activated receptor γ ; Pharmacophore modeling ; Quantitative structure– ; activity relationship ; In silico screening ; Type 2 diabetes mellitus
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：June 2011
• 年：2011
• 卷：46
• 期：6
• 页码：2513-2529
• 全文大小：1379 K

文摘

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) (r²₇₁ = 0.80, F = 270.3, r²_LOO = 0.73, r²_PRESS 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.