新型法尼基转移酶抑制剂的发现及构效关系分析  

Structure-activity relationship analysis of novel farnesyl transferase inhibitors

作　　者：张明 李诗良 朱丽丽 黄瑾 赵振江 李洪林 ZHANG Ming;LI Shi-liang;ZHU Li-li;HUANG Jin;ZHAO Zhen-jiang;LI Hong-lin(Shanghai Key Laboratory of New Drug Design,School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China)

机构地区：[1]华东理工大学药学院上海市新药设计重点实验室,上海200237

出　　处：《药学学报》2019年第1期111-116,共6页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金项目(21372078;81803437)

摘　　要：本文选择法尼基转移酶(FTase)作为靶标,利用计算机辅助药物设计Schr?dinger软件包中Glide v4.0程序进行虚拟筛选,获得了13个结构新颖、具备中等活性法尼基转移酶抑制剂(FTIs)苗头化合物。通过分析代表性化合物8 (IC_(50)=2.29μmol·L^(-1))和18 (IC_(50)=0.41μmol·L^(-1))与法尼基转移酶的结合模式,本文发现化合物8和18并未和Zn^(2+)鳌合,说明抑制剂中极性官能团与Zn^(2+)是否鳌合并未对酶抑制活性起到决定性作用。通过分析代表性化合物的预测结合模式与构效关系,本文发现的法尼基转移酶抑制剂(FTIs)苗头化合物仍具有改造空间,为进一步的结构优化并获得高活性和高选择性抑制剂奠定基础。Farnesyltransferase(FTase)was selected as a target for virtual screening of inhibitors using the Glide v4.0 program in the Schr?dinger software package.We discovered 13 novel structures as farnesyltransferase inhibitors(FTIs)with moderate potency.By analyzing the binding modes of representative compounds 8(2.29μmol·L^-1)and 18(0.41μmol·L^-1)with farnesyltransferase,it was found that compounds 8 and 18 didn’t coordinate with Zn^2+,indicating that the coordination between FTIs with Zn^2+ is not essential for the bioactivity of the inhibitors.The structure-activity relationship was summarized by analyzing the predicted binding modes of representative compounds.It was found that the scaffolds of the discovered FTIs had room for structural optimization which lay foundation for obtaining highly active and selective FTIs.

关 键 词：法尼基转移酶 抑制剂 虚拟筛选 构效关系分析 

分 类 号：R916[医药卫生—药学]