Microscopic binding of M5 muscarinic acetylcholine receptor with antagonists by homology modeling, molecular docking, and molecular dynamics simulation.
Microscopic binding of M5 muscarinic acetylcholine receptor with antagonists by homology modeling, molecular docking, and molecular dynamics simulation.
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DOI：
10.1021/jp210579b
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发表时间：
2012-01-12
影响因子：
3.3
通讯作者：
Zhani, Chang-Guo
中科院分区：
文献类型：
--
作者：
Huang, Xiaoqin;Zheng, Guangrong;Zhani, Chang-Guo
通过同源模建、分子对接和分子动力学（MD）模拟，我们建立了M5毒蕈碱乙酰胆碱受体（mAChR）的三维结构模型，以及M5 mAChR与拮抗剂SVT-40776和索利那新在脂双层和溶剂水环境中的两种复合物的三维结构模型。根据模拟结果，每种拮抗剂在由跨膜螺旋2、3和5至7形成的结合口袋中水平取向。每种拮抗剂的阳离子头基通过静电和氢键相互作用与带负电荷的残基Asp 110相互作用。模拟结果还揭示了SVT-40776和索利那新的结合模式之间的一些显着差异。特别是，SVT-40776与残基Tyr 458的侧链持续氢键键合，而索利那新不能与其羰基周围的残基形成类似的氢键。结合结构的这种显著差异与SVT-40776与M5 mAChR的结合亲和力（Kd = 0.4 nM）比索利那新与相同受体的结合亲和力（Kd = 31 nM）高得多的事实一致。计算的索利那新与SVT-40776的结合自由能变化（−2.3 ± 0.3 kcal/mol）与实验推导的结合自由能变化（−2.58 kcal/mol）非常一致，表明我们模拟的M5 mAChR结构及其与拮抗剂的复合物是可靠的。从这项计算研究中获得的新结构见解有望刺激未来对M5和其他亚型mAChR详细结构的进一步生化和药理学研究。
By performing homology modeling, molecular docking, and molecular dynamics (MD) simulations, we have developed three-dimensional (3D) structural models of M5 muscarinic acetylcholine receptor (mAChR) and two complexes for M5 mAChR binding with antagonists SVT-40776 and Solifenacin in the environment of lipid bilayer and solvent water. According to the simulated results, each of the antagonists is orientated horizontally in the binding pocket formed by transmembrane helices 2, 3, and 5 to 7. The cationic head group of each of the antagonists interacts wtih a negatively charged residue, Asp110, through electrostatic and hydrogen bonding interactions. The simulated results also reveal some significant difference between the binding modes of SVT-40776 and Solifenacin. In particular, SVT-40776 is persistently hydrogen-bonded with the side chain of residue Tyr458, whereas Solifenacin cannot form a similar hydrogen bond with residues around its carbonyl group. Such significant difference in the binding structures is consistent with the fact that SVT-40776 has a much higher binding affinity (Kd = 0.4 nM) with M5 mAChR than that of Solifenacin (Kd = 31 nM) with the same reeptor. The calculated binding free energy change (−2.3 ± 0.3 kcal/mol) from Solifenacin to SVT-40776 is in good agreement with the experimentally derived binding free energy change (−2.58 kcal/mol), suggesting that our modeled M5 mAChR structure and its complexes with the antagonists are reliable. The new structural insights obtained from this computational study are expected to stimulate future, further biochemical and pharmacological studies on the detailed structures of M5 and other subtypes of mAChRs.
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DOI：
10.1073/pnas.89.22.10915
发表时间：
1992-11-15
影响因子：
11.1
作者：
HENIKOFF, S;HENIKOFF, JG
通讯作者：
HENIKOFF, JG
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
8.8
作者：
Jonkam, Collette;Zhu, Yong;Cox, Robert A.
通讯作者：
Cox, Robert A.
影响因子：
16.2
作者：
BONNER, TI;YOUNG, AC;BUCKLEY, NJ
通讯作者：
BUCKLEY, NJ
DOI：
10.1124/jpet.109.152470
发表时间：
2009-08-01
影响因子：
3.5
作者：
Casarosa, Paola;Bouyssou, Thierry;Pieper, Michael
通讯作者：
Pieper, Michael