基于3D药效基团的计算机辅助设计探索新型TRPC 4抑制剂及其促进胰岛细胞增殖作用研究  

3D pharmacophore-based drug design,docking approaches to the discovery of the novel TRPC 4 inhibitor and the pro-proliferation effect on islet cells

作　　者：王洁 白小青 姚晓丹[2] 温敏[1] 马学玉 杨淬[1] WANG Jie;BAI Xiao-qing;YAO Xiao-dan;WEN Min;MA Xue-yu;YANG Cui(Key Laboratory of Chemistry in Ethnic Medicinal Resources,State Ethnic Affairs Commission ＆ Ministry of Education of China,Yunnan Minzu University,Kunming 650500,China;School of Mathematics and Computer Science,Yunnan Minzu University,Kunming 650500,China;Hospital of 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,云南昆明650500 [2]云南民族大学校医院,云南昆明650500 [3]云南民族大学数学与计算机学院,云南昆明650500

出　　处：《云南民族大学学报（自然科学版）》2018年第4期278-284,共7页Journal of Yunnan Minzu University:Natural Sciences Edition

基　　金：国家自然科学基金(81760655)

摘　　要：瞬时电位受体通道蛋白4(TRPC 4)与多种生理功能有关.拟通过计算机辅助筛选与细胞生物活性测定,寻找能与TRPC 4结合且具有潜在降血糖活性的新型化合物.通过一系列计算机辅助方法进行虚拟筛选,最终筛选出具有最优Hiphop药效基团模型且拟合良好的化合物作为此类化合物的选择范围.随后的细胞生物活性测定结果表明,化合物5对大鼠胰岛细胞的生长具有良好的促进作用(EC_(50)=20.7 nmol/L).同时,给药后大鼠胰岛细胞中TRPC 4在mRNA水平表达明显降低.研究结果表明,化合物5可能通过抑制TRPC 4的表达来刺激胰岛细胞的增殖.提供了TRPC 4选择性抑制剂缺乏的高效解决方案,并探讨了其具有成为糖尿病治疗新靶点的可能性.The canonical transient receptor potential 4（ TRPC 4） is implicated in diverse physiological functions.The present study was designed to investigate the novel TRPC 4 binding chemical compounds with potentially inhibitory effects through virtual screening methods and bioassay studies. Through a series of virtual screening methods,compounds with the top rank of the Hiphop pharmacophore model and good fitness were finally chosen as the identification of lead compounds. The follow-up bioassay studies showed that compound 5 promoted the growth of rat islet cells in a concentration-dependent manner（ EC_（50）= 20. 7 nmol/L）. Meanwhile,the mRNA expressions of TRPC 4 in rat islet cells were significantly decreased after the administration of compound 5. Our findings indicate that compound 5 may stimulate the growth of islet cells through the inhibition of TRPC 4. Meanwhile,the results of our study have solved the problem of lacking selective pharmacological inhibitors for TRPC 4 and revealed its potential as a therapeutic drug for diabetes mellitus.

关 键 词：计算机辅助药物设计 瞬时电位受体通道4 虚拟筛选 糖尿病 

分 类 号：R91[医药卫生—药学] TP391.7[自动化与计算机技术—计算机应用技术]