Bcl-X_L蛋白拮抗剂分子设计的研究进展  

Advances in molecular design of Bcl-X_L protein antagonists

作　　者：易享炎 何天同 曹臻 张婉玲 付豪亮 汪丽泽 于杨 黄和[1] 杨雅琼 黄菲 YI Xiangyan;HE Tiantong;CAO Zhen;ZHANG Wanling;FU Haoliang;WANG Lize;YU Yang;HUANG He;YANG Yaqiong;HUANG Fei(School of Pharmaceutical Sciences,Nanjing Tech University,Nanjing 211800,China)

机构地区：[1]南京工业大学药学院,江苏南京211800

出　　处：《生物加工过程》2018年第6期70-79,共10页Chinese Journal of Bioprocess Engineering

基　　金：江苏高校优秀科技创新团队计划(苏教科[2015]4号文);江苏省先进生物制造创新中心(XTC1810;XTE1850)

摘　　要：Bcl-X_L是Bcl-2家族蛋白重要的成员之一。作为细胞凋亡的关键效应因子,已成为目前最具吸引力的癌症治疗靶点之一。在介绍Bcl-2家族蛋白调控细胞凋亡机制的基础上,对近5年报道的新型Bcl-X_L蛋白拮抗剂的分子设计历程进行综述,着重阐述基于全新药物设计方法、高通量筛选、X线单晶衍射技术、计算机辅助药物设计以及衍生化修饰设计出的3类结构新颖、活性显著和靶向性优良的小分子肽模拟物。研究表明:苯甲酰脲类对Bcl-X_L蛋白具有极强的靶向性;磺酰胺类对Bcl-X_L蛋白的抑制活性可以达到纳摩尔水平;苯并噻唑类具有极佳的生物利用度。这3类分子骨架的设计代表了现代抗癌药物分子设计中三大发展方向,该研究将会对未来抗癌药物的研发提供借鉴,同时还对3类化合物作为Bcl-X_L蛋白拮抗剂的发展进行了展望。Bcl-XL is one of the most important members of the Bcl.2 family protein,and a most attractivetherapeutic target for cancer.Here,we review the molecular design of novel Bcl-XL protein antagonistsreported in the recent five years and the role of Bcl.2 family protein in apoptosis mechanism.Three novelsmall molecule peptides mimetic with novel activities and significant selectivity are designed based on thede novo drug design, high.throughput screening,X.ray diffraction crystallography, computer.aided drugdesign and receptor.based derivatization modification. Among them,benzoylurea has strong selectivity forBcl-XL protein; the inhibitory activity of sulfonamides on Bcl-XL protein can reach the nanomolar level;benzothiazoles have excellent bioavailability. The design of the molecular skeleton represents the threemajor directions in the design of modern pharmaceutical molecules. Finally, we also indicate futuredevelopment of these three kinds of compounds as antagonists of Bcl-XL protein.

关 键 词：BCL-XL 分子设计 苯甲酰脲骨架 磺酰胺骨架 苯并噻唑骨架 生物医学 

分 类 号：R914.2[医药卫生—药物化学]