Identification of pentacyclic triterpenes derivatives as potent inhibitors against glycogen phosphorylase based on 3D-QSAR studies

• DOI: 10.1016/j.ejmech.2011.02.053
• Publication Date: 2011-03-01T20:10:52Z
• Authors: Zhongjie Liang; Liying Zhang; Lianchun Li; Jun Liu; Hongling Li; Luyong Zhang; Limin Chen; Keguang Cheng; Mingyue Zheng; Xiaoan Wen; Pu Zhang; Jia Hao; Yanchun Gong; Xia Zhang; Xiaoyun Zhu; Jun Chen; Hong Liu; Hualiang Jiang; Cheng Luo; Hongbin Sun
• Keywords: Models, Molecular; 0301 basic medicine; Molecular Conformation; Quantitative Structure-Activity Relationship; Stereoisomerism; 3. Good health; 03 medical and health sciences; Animals; Glycogen Phosphorylase, Muscle Form; Rabbits; Enzyme Inhibitors; Muscle, Skeletal; Pentacyclic Triterpenes

Naturally occurring pentacyclic triterpenes (PT), a novel class of inhibitors against glycogen phosphorylase (GP), hold promise for the treatment of type-2 diabetes and other diseases with disorders in glycogen metabolism. To identify novel and more potent GP inhibitors, the receptor-based comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) approaches were performed to investigate the quantitative structure-activity relationships (QSAR) among 106 PT analogues. The validated models demonstrated that the elongated or bulky substitutions in C17 position and/or C2, C3 positions are favorable. Then based on the structural information extracted from these models, 56 derivatives were synthesized and biochemically tested in this study. The IC50 value of the most potent compound P50 was found to be 1.1 μM.