药学学报, 2019, 54(1): 111-116
引用本文:
张明, 李诗良, 朱丽丽, 黄瑾, 赵振江, 李洪林. 新型法尼基转移酶抑制剂的发现及构效关系分析[J]. 药学学报, 2019, 54(1): 111-116.
ZHANG Ming, LI Shi-liang, ZHU Li-li, HUANG Jin, ZHAO Zhen-jiang, LI Hong-lin. Structure-activity relationship analysis of novel farnesyl transferase inhibitors[J]. Acta Pharmaceutica Sinica, 2019, 54(1): 111-116.

新型法尼基转移酶抑制剂的发现及构效关系分析
张明, 李诗良, 朱丽丽, 黄瑾, 赵振江, 李洪林
华东理工大学药学院, 上海市新药设计重点实验室, 上海 200237
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Schrödinger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(IC50=2.29 μmol·L-1)和18(IC50=0.41 μmol·L-1)与法尼基转移酶的结合模式,本文发现化合物818并未和Zn2+鳌合,说明抑制剂中极性官能团与Zn2+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。
关键词:    法尼基转移酶      抑制剂      虚拟筛选      构效关系分析     
Structure-activity relationship analysis of novel farnesyl transferase inhibitors
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
Abstract:
Farnesyltransferase (FTase) was selected as a target for virtual screening of inhibitors using the Glide v4.0 program in the Schrödinger software package. We discovered 13 novel structures as farnesyltransferase inhibitors (FTIs) with moderate potency. By analyzing the binding modes of representative compounds 8 (IC50=2.29 μmol·L-1) and 18 (IC50=0.41 μmol·L-1) with farnesyltransferase, it was found that compounds 8 and 18 didn't coordinate with Zn2+, indicating that the coordination between FTIs with Zn2+ 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.
Key words:    farnesyltransferase    inhibitor    virtual screening    structure-activity relationship   
收稿日期: 2018-09-10
DOI: 10.16438/j.0513-4870.2018-0823
基金项目: 国家自然科学基金项目(21372078,81803437).
通讯作者: 李诗良,Tel:86-21-64253962,E-mail:zhjzhao@ecust.edu.cn;赵振江,Tel:86-21-64253962,E-mail:slli403@163.com
Email: zhjzhao@ecust.edu.cn;slli403@163.com
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