综合运用虚拟筛选三维定量构效关系模型发现潜在TRPC4配体（英文）  

Discovery of Potential Novel TRPC 4 Inhibitor by Combination of Virtual Screening and 3D-QSAR Modeling

作　　者：胡琳[1] 雷妍 李朋华 高俐 姚晓丹[4] 陈毅坚[1] 左之利[2] Hu Lin;Lei Yan;Li Penghua;Gao Li;Yao Xiaodan;Chen Yijian;Zuo Zhili(Ethnic Drug Screening&Pharmacology Center,Key Laboratory of Chemistry in Ethnic Medicinal Resources,State Ethnic Affairs Commission&Ministry of Education,Yunnan Minzu University,Kunming 650500,China;State Key Laboratory of Phytochemistry and Plant Resources in West China,Kunming Institute of Botany,Chinese Academy of Sciences,Kunming 650201,China;School of Chemical Engineering,Sichuan University of Science&Engineering,Zigong 643000,China;Hospital,Yunnan Minzu University,Kunming 650500,China)

机构地区：[1]云南民族大学民族药资源化学国家民委-教育部重点实验室,民族药活性筛选与药理学研究中心,昆明650500 [2]中国科学院昆明植物研究所,植物化学与西部植物资源持续利用国家重点实验室,昆明650201 [3]四川理工学院化工学院,自贡643000 [4]云南民族大学校医院,昆明650500

出　　处：《中南民族大学学报（自然科学版）》2018年第4期61-66,114,共7页Journal of South-Central University for Nationalities：Natural Science Edition

基　　金：国家自然科学基金资助项目(81460553,81760655);中科院战略先导项目(AXDA12030206)

摘　　要：瞬时感受器电位通道4(TRPC4)可能是一种调节人体生理和病理生理功能的关键靶点.通过计算机辅助药物设计和一系列虚拟筛选方法,结合Hiphop药效学团模型,筛选出一系列可能具有良好活性的的TRPC4配体化合物,并研究了这些化合物对大鼠胰岛细胞生长的影响.结果显示,其中新化合物7促进了大鼠胰岛细胞的生长,EC_(50)值为3.58μmol/L.然而,化合物7对被干扰了TRPC4表达的大鼠胰岛细胞的生长无显著性作用.与此同时,给予化合物7后,大鼠胰岛细胞TRPC4 mRNA的表达显著降低.因此,化合物7可能是一个潜在的TRPC4抑制剂,从而可能对糖尿病的治疗起到一定的作用.The modulation of canonical transient receptor potential 4(TRPC4)may be pivotal in diverse physiological and physiopathological functions in human.To investigate the potential therapeutical roles of novel TRPC4 ligands in diabetes mellitus,a series of compounds with the top rank of Hiphop pharmacophore model and with good fitness were chosen through computer-aided drug design and a series of virtual screening methods.Then,the effects of these compounds were evaluated by bioassay studies on the growth of rat islet cells.The novel compound 7 amoung these compounds promoted the growth of rat islet cells with an EC 50 value at 3.58μmol/L.However,compound 7 failed to show any effect on rat islet cells with TRPC4 knocked down.Meanwhile,the expressions of TRPC4 in mRNA level were significantly decreased after the administration of compound 7 in rat islet cells.Therefore,the therapeutical potential of compound 7 in diabetes mellitus may function through inhibiting TRPC4.

关 键 词：计算机辅助药物设计 瞬时感受器电位通道4 抑制剂 虚拟筛选 糖尿病 

分 类 号：Q455[生物学—生理学] R335.6[医药卫生—人体生理学]