原子尺度下研究G-四分体与小分子配体相互作用机制

项目名称： 原子尺度下研究G-四分体与小分子配体相互作用机制

项目编号： No.21473123

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 数理科学和化学

项目作者： 许维

作者单位： 同济大学

项目金额： 80万元

中文摘要： 以G-四链体为抗肿瘤药物作用靶点对化合物进行筛选和结构设计是目前化学和生物学领域密切关注的问题。理解G-四链体与小分子配体相互作用机制是设计特异靶向性药物的基础，也是目前研究的热点和难点。本申请项目拟利用超高真空扫描隧道显微镜（UHV-STM）高分辨成像及精准的操纵技术结合密度泛函理论（DFT）计算在原子尺度下系统研究小分子配体和G-四链体基本结构单元（G-四分体）的相互作用机制。UHV-STM可直接观测到小分子配体和G-四分体的结合方式，并可辨别小分子配体与G-四分体的作用位点，STM操纵技术可以从实验角度定性区分范德华力、氢键、配位键等不同作用力，结合DFT计算可定量研究上述各种作用力在形成小分子配体与G-四分体络合物中各自的作用。旨在通过本项目的研究，利用表面科学的方法探索和G-四链体有特异性结合能力的小分子配体结构信息，为筛选、设计、合成特异性靶向G-四链体的抗癌药物提供理论依据。

中文关键词： 扫描隧道显微镜；表面自组装；表面纳米结构；分子间相互作用；原子尺度

英文摘要： Currently, designing the compounds for the anticancer drug targets of the G-quadruplex is a hot research topic within the fields of chemistry and biochemistry. Understanding the nature of the interaction between G-quadruplex and the small molecular ligands is the basis of the specific targeted drug design, which is also the difficulty with the current research. This suggested proposal is intended to use ultra-high vacuum scanning tunneling microscope (UHV-STM) high-resolution imaging and delicate STM manipulation technique combining with density functional theory (DFT) calculations to systematically study the mechanism of the interactions between the unit of G-quadruplex (i.e. G-quartet) and small molecular ligands at the atomic scale. UHV-STM can directly observe the way of interaction between small molecular ligands and G-quartets, and moreover it can distinguish the interaction points between small molecular ligands and G-quartets. STM manipulations could experimentally differentiate vdW force, hydrogen bonding, and coordination bonding within the formed structures. By combination of DFT calculations we can quantify the respective roles of the above-mentioned different interactions in the formation of a complex structure of small molecular ligands and G-quartets. With this proposed research we aim to explore the structural information of small molecular ligands that have specific binding ability with G-quadruplex, which will provide further insight into theoretical basis and guidance on designing, and synthesizing anticancer drugs that specifically target G-quadruplex.

英文关键词： scanning tunneling microscope;surface self-assembly;surface nanostructure;molecular interaction;atomic scale