基于Topomer CoMFA方法的苯基哌嗪类5-HT_7受体拮抗剂的3D-QSAR研究
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摘要
5-HT_7受体是5-HT受体家族成员之一,主要参与体温、睡眠和情感性精神障碍的调节,5-HT_7受体拮抗剂已成为开发新型抗抑郁药物的一个重要思路。本文使用Sybyl-X2.0软件中的Topomer CoMFA方法对苯基哌嗪类5-HT_7受体拮抗剂进行三维定量构效关系分析。首先以苯基哌嗪作为母核,对化合物进行切割,得到4个R基片段,再通过自动叠合每个R基片段,分别计算所产生的静电场和立体场,最后得到了该类化合物作为5-HT_7受体拮抗剂的3D-QSAR模型。其交叉验证相关系数q~2为0.744,非交叉验证相关系数r~2为0.871,表明该模型稳定可靠,具有较好的预测能力。根据QSAR模型的结果在化合物29的基础上进行分子设计,得到了一些可能具有较高活性及成药性的化合物,该QSAR模型的研究结果可为新型5-HT_7受体拮抗剂的设计提供参考。
5-HT_7 receptor is a member of the 5-HT receptor family, mainly involved in the regulation of body temperature, sleep and affective disorders. The inhibition of 5-HT_7 receptor has become an important strategy to develop new antidepressants. As a class of 5-HT_7 receptor antagonists, 36 phenyl-piperazines were applied to 3 D-quantitative structure activity relationship analysis by Topomer CoMFA method. And 3 D-QSAR model was generated by Sybyl-X2.0 package as follow: Firstly, reasoning cutting was performing based on the skeleton structure of phenyl-piperazine to generate four R groups. Then, the steric and electrostatic fields of each R groups were calculated separately after automatic superimposition. Finally, the 3 D-QSAR model was gained with the coefficient q~2 of cross validation was 0.744 and the coefficient r~2 of non-cross validation was 0.871, which indicating that the model has good reliability and predictive ability. According to the results of QSAR analysis, 12 new molecules were designed based on the structure of compound 29. Some newly designed compounds exhibited higher activity and improved drug-likeness, indicating that the QSAR results can provide an important reference for the rational design of novel 5-HT_7 receptor antagonists.
5-HT_7 receptor is a member of the 5-HT receptor family, mainly involved in the regulation of body temperature, sleep and affective disorders. The inhibition of 5-HT_7 receptor has become an important strategy to develop new antidepressants. As a class of 5-HT_7 receptor antagonists, 36 phenyl-piperazines were applied to 3 D-quantitative structure activity relationship analysis by Topomer CoMFA method. And 3 D-QSAR model was generated by Sybyl-X2.0 package as follow: Firstly, reasoning cutting was performing based on the skeleton structure of phenyl-piperazine to generate four R groups. Then, the steric and electrostatic fields of each R groups were calculated separately after automatic superimposition. Finally, the 3 D-QSAR model was gained with the coefficient q~2 of cross validation was 0.744 and the coefficient r~2 of non-cross validation was 0.871, which indicating that the model has good reliability and predictive ability. According to the results of QSAR analysis, 12 new molecules were designed based on the structure of compound 29. Some newly designed compounds exhibited higher activity and improved drug-likeness, indicating that the QSAR results can provide an important reference for the rational design of novel 5-HT_7 receptor antagonists.
引文
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2 Canale V,Partyka A,Kurczab R,et al.Novel 5-HT7Rantagonists,arylsulfonamide derivatives of(aryloxy)propyl piperidines:add-on effect to the antidepressant activity of SSRI and DRI,and procognitive profile[J].Bioorganic&Medicinal Chemistry,2017,349(12):889-903.
3 Leiser SC,Li Y,Pehrson AL,et al.Serotonergic regulation of prefrontal cortical circuitries involved in cognitive processing:a review of individual 5-HTreceptor mechanisms and concerted effects of 5-HTreceptors exemplified by the multimodal antidepressant vortioxetine[J].ACS Chemical Neuroscience,2015,6(7):970-986.
4 Kattula RVR,Penugonda V,Ravisankar P,et al.A brief summary on vortioxetine[J].World Journal of Pharmaceutical Research,2014,3(9):1313-1336.
5 Mansari M El,Belblidia H,Didier A,et al.Pharmacological blockade of 5-HT7 receptors as a putative fast acting antidepressant strategy[J].Neuropsychopharmacology,2011,36(6):1275-1288.
6徐丽丽,陈春林.5-HT7受体与抑郁症相关研究进展[J].宜春学院学报,2015,37(6):71-73.
7仝建波,王洋,雷珊,等.R基团搜索技术用于硫代氨基甲酸酯类非核苷类逆转录酶抑制剂的分子设计[J].计算机与应用化学,2018,35(02):115-125.
8 Kucwajbrysz K,Kurczab R,Jastrz?bskawi?sek M,et al.Computer-aided insights into receptor-ligand interaction for novel 5-arylhydantoin derivatives as serotonin 5-HT7 receptor agents with antidepressant activity[J].European Journal of Medicinal Chemistry,2018,147:102-114.
9 Kim Y,Park H,Lee J,et al.5-HT7 receptor modulators:amino groups attached to biphenyl scaffold determine functional activity[J].European Journal of Medicinal Chemistry,2016,123:180-190.
10 Partyka A,Kurczab R,Canale V,et al.The impact of the halogen bonding on D2 and 5-HT1A/5-HT7 receptor activity of azinesulfonamides of 4-[(2-ethyl)piperidinyl-1-yl]phenylpiperazines with antipsychotic and antidepressant properties[J].Bioorganic&Medicinal Chemistry,2017,25(14):3638-3648.
11 Gunda S K,Narasimha S K M,Madasu A M L,et al.5-HT7 receptor ligands:A 3D-QSAR CoMFA and Co MSIA analysis of quinazolinone derivatives[J].International Journal of Pharmaceutical Sciences Review&Research,2013,22(1):84-91.
12 Kim Y,Kim J,Tae J,et al.Discovery of aryl-biphenyl-2-yl-methylpiperazines as novel scaffolds for 5-HT7ligands and role of the aromatic substituents in binding to the target receptor[J].Bioorganic&Medicinal Chemistry,2013,21(9):2568-2576.
13 Sagnes C,Fournet G,Satala G,et al.New 1-arylindoles based serotonin 5-HT7 antagonists.synthesis and binding evaluation studies[J].European Journal of Medicinal Chemistry,2014,75:159-168.
14祝丽萍.计算机辅助5-HT3受体拮抗剂的设计[D].复旦大学,2006.
15 Roy K,Kar S.The rm2 metrics and regression through origin approach:reliable and useful validation tools for predictive QSAR models(Commentary on'Is regression through origin useful in external validation of QSAR models?')[J].European Journal of Pharmaceutical Sciences,2014,62:111-114.
16 Golbraikh A,Tropsha A.Beware of q2[J].Journal of Molecular Graphics&Modelling,2002,20(4):269-276.
17覃礼堂,刘树深,肖乾芬,等.QSAR模型内部和外部验证方法综述[J].环境化学,2013,32(07):1205-1211.
18 Latacz G,Lubelska A,Jastrz?bska-Wi?sek M,et al.In the search for a lead structure among series of potent and selective hydantoin 5-HT7 R agents:the drug-likeness in vitro study[J].Chemical Biology&Drug Design,2017,90(6):1295-1306.
19郑春松,付长龙,叶锦霞,等.计算机模拟预测川芎与当归的药代动力学和肝毒性特征[J].福建中医药,2018,49(01):23-25.
20 El-Gamal K M,El-Morsy A M,Saad A M,et al.Synthesis,docking,QSAR,ADMET and antimicrobial evaluation of new quinoline-3-carbonitrile derivatives as potential DNA-gyrase inhibitors[J].Journal of Molecular Structure,2018,1166:15-33.