Pharmacophore Identification for Peroxisome Proliferator-Activated Receptor Gamma Agonists

Bulletin of the Korean chemical society

Keun Woo Lee¹  Hyong Ha Kim¹  Young sik Sohn¹  Songmi Kim¹  Jung Keun Suh¹  Swan Hwang¹  Yuno Lee¹  Ayoung Baek¹  Chanin Park¹  Minky Son¹ 

关键词: Peroxisome proliferator activated receptor γ (PPARγ);    Computer-aided drug design;    Pharmacophore model;    Virtual screening;    Molecular docking;   

DOI  :  

学科分类：化学（综合）

来源: Korean Chemical Society

【 摘 要 】

Peroxisome proliferator-activated receptors (PPARs) are members of nuclear receptors and their activation induces regulation of fatty acid storage and glucose metabolism. Therefore, the PPARγ is a major target for the treatment of type 2 diabetes mellitus. In order to generate pharmacophore model, 1080 known agonists database was constructed and a training set was selected. The Hypo7, selected from 10 hypotheses, contains four features: three hydrogen-bond acceptors (HBA) and one general hydrophobic (HY). This pharmacophore model was validated by using 862 test set compounds with a correlation coefficient of 0.903 between actual and estimated activity. Secondly, CatScramble method was used to verify the model. Hence, the validated Hypo7 was utilized for searching new lead compounds over 238,819 and 54,620 chemical structures in NCI and Maybridge database, respectively. Then the leads were selected by screening based on the pharmacophore model, predictive activity, and Lipinski’s rules. Candidates were obtained and subsequently the binding affinities to PPARγ were investigated by the molecular docking simulations. Finally the best two compounds were presented and would be useful to treat type 2 diabetes.

【 授权许可】

Unknown