Unbinding Pathways of GW4064 from Human Farnesoid X Receptor As Revealed by Molecular Dynamics Simulations
文献类型：期刊论文
| 作者 | Li, Weihua1,2; Fu, Jing1; Cheng, Feixiong1; Zheng, Mingyue2 ; Zhang, Jian3; Liu, Guixia1; Tang, Yun1
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| 刊名 | JOURNAL OF CHEMICAL INFORMATION AND MODELING
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| 出版日期 | 2012-11 |
| 卷号 | 52期号:11页码:3043-3052 |
| ISSN号 | 1549-9596 |
| DOI | 10.1021/ci300459k |
| 文献子类 | Article |
| 英文摘要 | 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 |
| WOS关键词 | THYROID-HORMONE RECEPTORS ; RETINOIC ACID RECEPTOR ; LIGAND-BINDING DOMAIN ; NUCLEAR RECEPTOR ; CLINICAL-APPLICATIONS ; MEDICINAL CHEMISTRY ; RANDOM ACCELERATION ; ESTROGEN-RECEPTOR ; RELEASE PATHWAYS ; FXR AGONISTS |
| 资助项目 | State Key Laboratory of Drug Research[SIMM1106KF-07] ; National Natural Science Foundation of China[21072059] ; Shanghai Committee of Science and Technology[11DZ2260600] ; Scientific Research Foundation for the Returned Overseas Chinese Scholars, Ministry of Education of China[00000000] |
| WOS研究方向 | Pharmacology & Pharmacy ; Chemistry ; Computer Science |
| 语种 | 英语 |
| WOS记录号 | WOS:000311461400024 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277884]  |
| 专题 | 药物发现与设计中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Zheng, Mingyue |
| 作者单位 | 1.E China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai 200237, Peoples R China; 2.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 3.Shanghai Jiao Tong Univ, Shanghai Key Lab Tumor Microenvironm & Inflammat, Sch Med, Shanghai 200025, Peoples R China |
| 推荐引用方式 GB/T 7714 | Li, Weihua,Fu, Jing,Cheng, Feixiong,et al. Unbinding Pathways of GW4064 from Human Farnesoid X Receptor As Revealed by Molecular Dynamics Simulations[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING,2012,52(11):3043-3052. |
| APA | Li, Weihua.,Fu, Jing.,Cheng, Feixiong.,Zheng, Mingyue.,Zhang, Jian.,...&Tang, Yun.(2012).Unbinding Pathways of GW4064 from Human Farnesoid X Receptor As Revealed by Molecular Dynamics Simulations.JOURNAL OF CHEMICAL INFORMATION AND MODELING,52(11),3043-3052. |
| MLA | Li, Weihua,et al."Unbinding Pathways of GW4064 from Human Farnesoid X Receptor As Revealed by Molecular Dynamics Simulations".JOURNAL OF CHEMICAL INFORMATION AND MODELING 52.11(2012):3043-3052. |
入库方式： OAI收割
来源：上海药物研究所
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