Binding mechanism of nine N-phenylpiperazine derivatives and α1A-adrenoceptor using site-directed molecular docking and high performance affinity chromatography
Binding mechanism of nine N-phenylpiperazine derivatives and α1A-adrenoceptor using site-directed molecular docking and high performance affinity chromatography
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DOI：
10.1039/c5ra10812h
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发表时间：
2015-01-01
期刊：
影响因子：
3.9
通讯作者：
Zheng, X. H.
中科院分区：
文献类型：
--
作者：
Zhao, X. F.;Wang, J.;Zheng, X. H.
n -苯哌嗪衍生物通过介导α(1)-肾上腺素能受体的信号通路，被广泛用作治疗心血管系统相关疾病的临床药物。利用分子对接和高效亲和层析技术探讨了9种n -苯基哌嗪衍生物与α (1A)-肾上腺素受体的结合机制。方法包括对α (1A)-肾上腺素受体的三维结构进行同源性建模，利用LIBDOCK预测其结合行为，并通过正面分析研究其结合的热力学行为。分子对接结果显示，受体的Asp（106）、Gln（177）、Ser（188）、Ser（192）和Phe（193）是9种n -苯基哌嗪衍生物与α (1A)-肾上腺素受体结合的主要结合位点。这种结合是由氢键的形成和静电力驱动的。这些衍生物对受体的亲和力取决于可电离哌嗪的官能团、氢键受体和配体结构中的疏水部分。正面分析表明，这些化合物与受体的缔合常数由它们在上述官能团上的结构偏差决定。热力学研究显示焓和吉布斯自由能变化为负，熵变化为正，证明衍生物与α (1A)-肾上腺素受体的结合主要是由静电力驱动的。这一结果与分子对接预测的结合机制一致。利用受体色谱法可以探索候选药物特异性结合α (1A)-肾上腺素能受体的结合机制。
N-Phenylpiperazine derivatives are widely used as clinical drugs for fighting diseases related to the cardiovascular system by mediating the signal pathway of alpha(1)-adrenoceptor. The binding mechanism of nine N-phenylpiperazine derivatives to alpha(1A)-adrenoceptor was explored using molecular docking and high performance affinity chromatography. The methodology involved homology modelling of the three dimensional structure of alpha(1A)-adrenoceptor, predication of the binding behaviors using LIBDOCK and investigation of the thermodynamic behaviors of the binding by frontal analysis. Molecular docking results showed that Asp(106), Gln(177), Ser(188), Ser(192) and Phe(193) of the receptor were the main binding sites for the nine N-phenylpiperazine derivatives binding to alpha(1A)-adrenoceptor. The binding was driven by formation of hydrogen bonds and electrostatic forces. The affinity of these derivatives for the receptor depended on the functional groups of an ionizable piperazine, hydrogen bond acceptor and hydrophobic moiety in the ligand structures. Frontal analysis indicated that the association constants of these compounds for the receptor were determined by their structural deviations in the above-mentioned functional groups. Thermodynamic studies presented negative enthalpy and Gibbs free energy changes with a positive entropy change, providing proof that the binding of the derivatives to alpha(1A)-adrenoceptor was mainly driven by electrostatic forces. This result was in line with the binding mechanism predicted by molecular docking. It is possible to explore the binding mechanism of drug candidates specifically binding to alpha(1A)-adrenoceptor using receptor chromatography.