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-HT7 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-HT7 receptor has become an important strategy to develop new antidepressants.As a class of 5-HT7 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 q2 of cross validation was 0.744 and the coefficient r2 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-HT7 receptor antagonists.
作者
莫贤炜
周海燕
李晓雷
李媛媛
李晶
MO Xianwei;ZHOU Haiyan;LI Xiaolei;LI Yuanyuan;LI Jing(School of Bioscience and Bioengineering,South China University of Technology,Guangzhou 510006,Guangdong,China)
出处
《计算机与应用化学》
CAS
北大核心
2018年第8期667-679,共13页
Computers and Applied Chemistry
基金
广东省省级科技计划资助项目(No.2015A020211005)
