Affinity of aporphines for the human 5-HT2A receptor: insights from homology modeling and molecular docking studies.
Affinity of aporphines for the human 5-HT2A receptor: insights from homology modeling and molecular docking studies.
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DOI：
10.1016/j.bmc.2010.06.043
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发表时间：
2010-08-01
影响因子：
3.5
通讯作者：
Harding, Wayne W.
中科院分区：
文献类型：
--
作者：
Pecic, Stevan;Makkar, Pooja;Chaudhary, Sandeep;Reddy, Boojala V.;Navarro, Hernan A.;Harding, Wayne W.
利用ICM Pro、GLIDE和GOLD对接方法将南替宁类似物对接到人5-HT 2A受体的模型结构中。所得对接分数用于与观察到的体外表观亲和力（Ke）数据相关。GOLD对接算法与5-HT 2A的同源性模型一起使用时，基于牛视紫红质模板并由程序MODELLER构建，给出了与体外结果最一致的结果。进一步分析的对接姿态之间的一个C1烷基系列的南替宁类似物的成员，表明它们结合到受体在一个类似的方向，但不同于南替宁。除了C1烷基类似物的质子化氮与残基Asp 155之间的重要相互作用之外，我们还鉴定了Ser 242、Phe 234和Gly 238作为负责这些化合物对5-HT 2A受体的亲和力的关键残基。具体地，这些类似物中的一些与Ser 242建立H-键以及与Phe 234和Gly 238建立疏水相互作用的能力似乎解释了它们与nantenine相比增强的亲和力。
Analogs of nantenine were docked into a modeled structure of the human 5-HT2A receptor using ICM Pro, GLIDE and GOLD docking methods. The resultant docking scores were used to correlate with observed in vitro apparent affinity (Ke) data. The GOLD docking algorithm when used with a homology model of 5-HT2A, based on a bovine rhodopsin template and built by the program MODELLER, gives results which are most in agreement with the in vitro results. Further analysis of the docking poses among members of a C1 alkyl series of nantenine analogs, indicate that they bind to the receptor in a similar orientation, but differently than nantenine. Besides an important interaction between the protonated nitrogen of the C1 alkyl analogs and residue Asp155, we identified Ser242, Phe234 and Gly238 as key residues responsible for the affinity of these compounds for the 5-HT2A receptor. Specifically, the ability of some of these analogs to establish a H-bond with Ser242 and hydrophobic interactions with Phe234 and Gly238 appears to explain their enhanced affinity as compared to nantenine.
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