文献类型：期刊文献

英文题名：Refinement and 3D-QSAR Studies of Inhibitors of Cyclophilin A Containing Amide Linker

作者：Fan, Feng[1,2];Zhu, Jin[1];Ni, Shuaishuai[1];Cheng, Jiagao[1,2];Tang, Yun[1];Kang, Congmin[3];Li, Jian[1];Jiang, Hualiang[1,4]

机构：[1]E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China;[2]E China Univ Sci & Technol, Shanghai Key Lab Chem Biol, Shanghai 200237, Peoples R China;[3]Qingdao Univ Sci & Technol, Coll Chem Engn, Qingdao 260042, Peoples R China;[4]Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China

年份：2009

卷号：28

期号：2

起止页码：183

外文期刊名：QSAR & COMBINATORIAL SCIENCE

收录：;EI(收录号：20241916061609);WOS:【SCI-EXPANDED(收录号:WOS:000263587800004)】；

基金：The financial supports from the 863 Hi-Tech Program of China (grant 2006AA020404), Shanghai Rising-Star Program (A type) of Shanghai Ministry of Science and Technology (grant 07QA14013), the National Natural Science Foundation of China (grants 20802018 and 20772070), and the Natural Science Foundation of Shanghai (grant 08ZR1406500) are acknowledged.

语种：英文

外文关键词：Amide linker; 3D-QSAR; CoMFA; CoMSIA; CypA

摘要：Cyclophilin A (CypA) is a ubiquitous cellular enzyme playing essential role in many biological processes, and the discovery of CypA inhibitor is now of special interest in the treatment of immunological disorders. In this work, molecular modeling studies were performed to develop a predictive Common Pharmacophore Hypothesis (CPH) and use it for alignment in 3D-QSAR studies using CoMFA and CoMSIA. A total of 30 compounds containing an amide fragment as the key linker, consisting of 17 of our previously discovered CypA inhibitors and 13 other inhibitors reported in the literature, were selected for pharmacophore refinement and 3D-QSAR studies. The best pharmacophore hypothesis AADR, which had two hydrogen bond acceptors, a hydrogen bond donor, and an aromatic ring, was obtained and used for the alignment of molecules in CoMFA and CoMSIA model development. The models showed a good r(2) value of 0.992 and 0.949 for CoMFA and CoMSIA, respectively. The contour maps of the models were analyzed to give structural insight for activity improvement of future novel CypA inhibitors. The CPH can also provide a powerful template for virtual screening and design of new CypA inhibitors.