喜树碱构象的量子化学研究及其与晶体结构的比较  

Conformational Analysis of Camptothecin Using the Quantum Chemical Methods and Comparison with the X-ray Structure

作　　者：宋云龙[1] 张万年[1] 季海涛[1] 周有骏[1] 朱驹[1] 吕加国[1] 

机构地区：[1]中国人民解放军第二军医大学药学院,上海200433

出　　处：《中国药物化学杂志》2001年第4期187-192,共6页Chinese Journal of Medicinal Chemistry

基　　金："973"国家重点基础研究项目子项目 (G1 9980 5 1 1 0 4 );国家自然科学基金项目 (3 9970 874 )

摘　　要：喜树碱类抗肿瘤药物是临床广泛使用的经典的作用于DNA拓扑异构酶Ⅰ的特异性抑制剂。已有的喜树碱构象研究结果彼此并不一致 ,而采用可靠方法进行构象研究是阐明该药物作用模式的关键一环。本文在分子动力学搜寻喜树碱构象空间的基础上 ,采用量子化学的半经验AM1、PM3方法和abinitio的RHF/3 2 1G、RHF/6 3 1G方法对近似晶体结构构象的分子力学构象进行了系统优化。所得构象均采用密度泛函方法B3LYP/6 3 1G(d)进行单点能计算 ,并和喜树碱碘乙酸酯的晶体结构进行了比较。结果表明 ,abinitio方法得到的构象更接近晶体结构构象 ,而半经验方法得到的构象接近初始的分子力学构象。abinitio方法研究表明喜树碱E环内酯部分形成分子内氢键 ,使E环内酯键反应性提高 ,可与TopoI-DNA共价复合物形成较好的相互作用 。Camptothecin(CPT)compounds are specific inhibitors o f DNA topoisomerase Ⅰ(TopoI)and have been widely used in the clinic.Previo us conformational studies of CPT were inconsistent with each other.It′s nec essar y to apply reliable computational method to conformational studies to elucidate the mode of action of the drug.Based on the conformational space sampling using the molecular dynamic techniques,the molecular mechanics conformation of CPT similar to that of the crystal structure were optimized by ab initio calculations at th e Hartree-Fock level(HF/3-21G and HF/6-31G)as well as by semi-empirical AM1?P M3 calculations in this study.The resulting conformations were calculated using the density functional method B3LYP/6-31G(d)and were also compared with the X- r ay crystallographic studies.It has been indicated that the conformations optimiz ed by ab initio studies are much more similar to that obtained by the X-ray cry stallographic studies,rather than the starting conformation obtained with molecu lar mechanics.However,the conformations optimized by the semi-empirical studies are much more similar to the starting conformation.It is also shown that ab ini tio studies are able to predict intramolecular hydrogen bond,while semi-empiric al studies give poor results.The formation of intramolecular hydrogen bond resul ts from high reactivity of E-ring,which is propitious for CPT to make interacti on with TopoI-DNA and is also apt to hydrolyze by the solvent effects of water.

关 键 词：喜树碱 拓扑异构酶Ⅰ 分子构象 分子内氢键 

分 类 号：R914[医药卫生—药物化学]