文献类型：期刊文献

英文题名：Unbinding Pathways of GW4064 from Human Farnesoid X Receptor As Revealed by Molecular Dynamics Simulations

作者：Li, Weihua[1,2];Fu, Jing[2];Cheng, Feixiong[2];Zheng, Mingyue[1];Zhang, Jian[3];Liu, Guixia[2];Tang, Yun[2]

机构：[1]Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;[2]E China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai 200237, Peoples R China;[3]Shanghai Jiao Tong Univ, Shanghai Key Lab Tumor Microenvironm & Inflammat, Sch Med, Shanghai 200025, Peoples R China

年份：2012

卷号：52

期号：11

起止页码：3043

外文期刊名：JOURNAL OF CHEMICAL INFORMATION AND MODELING

收录：;EI(收录号：20124815741071);WOS:【SCI-EXPANDED(收录号:WOS:000311461400024)】；

基金：This work was supported by the State Key Laboratory of Drug Research (SIMM1106KF-07), the National Natural Science Foundation of China (Grant 21072059), the Shanghai Committee of Science and Technology (Grant 11DZ2260600), and the Scientific Research Foundation for the Returned Overseas Chinese Scholars, Ministry of Education of China.

语种：英文

外文关键词：Physiology - Crystal structure - Ligands - Computational chemistry

摘要：Farnesoid X receptor (FXR, NR1H4) is a member, of a nuclear receptor superfamily, Which plays important roles in bile, acid homeostasis lipoprotein and glucose metabolism, and hepatic regeneration. GW4064 is a potent and selective FXR agonist and has become a tool compound to probe the physiological functions of FXR. Until now, the mechanism of GW4084-entering and leaving the FXR pocket.,is still poorly understood.,Here; we report a computational study of GW4064 unbinding pathways from FXR by using several molecular dynamics (MD) simulation techniques. Based on the crystal structure of FXR in complex With GW4064 conventional MD was first used to refine the: binding, and check the stability of GW4064 in the FXR pocket Random acceleration MD simulations were then performed to explore the possible unbinding, pathways of GW4064, from FXR. Four main pathway clusters were found, among Which: three subpathways, namely Paths 2A, 2B, and 1B, were : observed most frequently Multiple steered MD simulations Were further employed to estimate the maximum rupture force and the sum of the forces and to characterize the intermediate states of the ligand unbinding process. By comparing the average force profiles and structural changes, Paths 2A and 2B were identified to 150 the Most favorable unbinding pathways. The former is located between the H1-H2 loop, and the H5-H6 loop, and the latter is located in the cleft formed by the E5H6-looP,:H6; and H7. Moreover, the residues;lining the pathways were analyzed for their roles in ligand unbinding. Based on our results, the possible structural modification strategies on GW4064 were also proposed