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首页> 外文期刊>Physical chemistry chemical physics: PCCP >The binding mode of vilazodone in the human serotonin transporter elucidated by ligand docking and molecular dynamics simulations
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The binding mode of vilazodone in the human serotonin transporter elucidated by ligand docking and molecular dynamics simulations

机译：通过配体对接和分子动力学模拟阐明的人血清素转运蛋白中的vilazodone的结合模式

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摘要

Vilazodone is a novel antidepressant used for the treatment of major depressive disorder (MDD) with a primary action mechanism of inhibiting the human serotonin reuptake transporter (hSERT) and acting as a 5-HT1A receptor partial agonist. The interaction between vilazodone and the 5-HT1A receptor has been reported, however, the binding mode of vilazodone in the hSERT remains elusive. In the current study, to elucidate the molecular mechanism of vilazodone binding in the hSERT, the drug and its five analogs were docked into the hSERT crystal structure as initial conformations and were sampled by 400 ns molecular dynamics (MD) simulations. Through the analysis of the profiles of protein-ligand binding free energies, interaction fingerprints, and conformational rearrangements, the binding mode of vilazodone in the hSERT was revealed. As a result, unlike the classical antidepressants located in the S1 site of the hSERT, vilazodone adopted a linear pose in the binding pocket. Its arylpiperazine fragment occupies the central site (S1) and interacts with Y95, D98, I172, Y176, F335, F341, S438, and T439, while the indole fragment extends to the allosteric site (S2) via interacting with the ionic switch (R104/E403) between the two sites. The new insights obtained are not only helpful in understanding the binding mode of vilazodone in the hSERT, but also provide valuable guidance to the discovery of novel antidepressant drugs.
机译：Vilazodone是一种新型抗抑郁药，用于治疗主要抑郁症（MDD），其主要作用机制抑制人血清素再摄取转运蛋白（HSERT）并作为5-HT1A受体部分激动剂作用。然而，已经报道了vilazodone和5-HT1A受体之间的相互作用，然而，HSERT中的vilazodone的结合模式仍然难以捉摸。在目前的研究中，为了阐明HSERT中的vilazodone结合的分子机制，将药物及其五种类似物停靠在HSERT晶体结构中作为初始构象，并通过400ns分子动力学（MD）模拟来取样。通过分析蛋白质 - 配体粘合剂的曲线，相互作用指纹和构象重排，揭示了HSERT中的VILAZODONE的结合模式。结果，与位于HSERT的S1位点的古典抗抑郁药不同，Vilazodone采用粘合口袋中的线性姿势。其芳基哌嗪片段占据中心部位（S1）并与Y95，D98，I172，Y176，F335，F341，S438和T439相互作用，而吲哚片段通过与离子开关相互作用（R104）延伸到变构位点（S2）（R104 / E403）在两个站点之间。所获得的新见解不仅有助于了解HSERT中Vilazodone的结合模式，而且还提供了对新型抗抑郁药物的发现的宝贵指导。

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    Zhang Yang; Zheng Guoxun; Fu Tingting; Hong Jiajun; Li Fengcheng; Yao Xiaojun; Xue Weiwei; Zhu Feng;

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    Chongqing Univ Sch Pharmaceut Sci Chongqing 401331 Peoples R China;

    Chongqing Univ Sch Pharmaceut Sci Chongqing 401331 Peoples R China;

    Chongqing Univ Sch Pharmaceut Sci Chongqing 401331 Peoples R China;

    Zhejiang Univ Coll Pharmaceut Sci Hangzhou 310058 Peoples R China;

    Zhejiang Univ Coll Pharmaceut Sci Hangzhou 310058 Peoples R China;

    Lanzhou Univ State Key Lab Appl Organ Chem Lanzhou 730000 Peoples R China;

    Chongqing Univ Sch Pharmaceut Sci Chongqing 401331 Peoples R China;

    Chongqing Univ Sch Pharmaceut Sci Chongqing 401331 Peoples R China;

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  • 正文语种 eng
  • 中图分类 物理学;化学;
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