靶向C-kit1 DNA G-四链体凹槽的选择性探针分子设计

项目名称： 靶向C-kit1 DNA G-四链体凹槽的选择性探针分子设计

项目编号： No.21502060

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 环境科学、安全科学

项目作者： 位灯国

作者单位： 华中农业大学

项目金额： 21万元

中文摘要： 作用于DNA G-四链体的小分子显示了很强的抗肿瘤活性，但这些小分子对不同基因上的G-四链体缺乏选择性，不利于对特定基因的表达进行选择性调控。这主要是因为这些小分子大多作用于G-四链体公共的鸟嘌呤碱基平面。C-kit1 DNA G-四链体中结构独特的凹槽在所有G-四链体结构中显得十分特别，引起了广泛的关注。该凹槽在晶体和溶液状态下都能稳定存在，并且其空间和电荷性质均有利于配体小分子的结合。靶向C-kit1 DNA G-四链体凹槽的小分子可专一性地稳定C-kit1 DNA G-四链体，从而选择性地抑制C-kit蛋白的表达。本项目将综合使用计算模拟筛选、生物物理检测和碎片分子浸泡等研究手段，期望找到对C-kit1 DNA G-四链体凹槽及与其相连的沟进行识别的碎片小分子;并通过组合药效团搜索、碎片分子拼接等方法设计选择性作用于C-kit1 DNA G-四链体的小分子。

中文关键词： DNA；G-四链体；C-kit1；；选择性识别；凹槽；小分子

英文摘要： The ligands targeting DNA G-quadruplex showed great potential against the tumor cells. However, being lack of selectivity on G-quadruplexes from different genes, these ligands failed at mediating the expression of a specific gene. This is mainly due to the fact that most of the ligands interact with the G-quartet surface, which is common to different DNA G-quadruplex structures. Special attention is attracted to the cleft in the C-kit1 DNA quadruplex structure, whose stability in crystal and solution, the space and the charge distribution show its potential as a ligand target. The ligands targeting the special cleft could selectively prevent the expression of c-kit protein by selectively stabilizing the c-kit1 DNA quadruplex. Through virtual screening, biophysical assay and fragment soaking, some fragment molecules are expected to be discovered to bind with the special cleft and the connected grooves, respectively. Pharmacophore combination and fragment molecular linking could be used to search for new fragments and to link the fragements to obtain liands with high selectivity.

英文关键词： DNA G-quadruplex;C-kit1 ;recognition with selectivity;cleft;small molecule