基于RDV P2,P3蛋白靶标抗水稻矮缩病毒先导化合物的设计合成与构效关系

项目名称： 基于RDV P2,P3蛋白靶标抗水稻矮缩病毒先导化合物的设计合成与构效关系

项目编号： No.21302002

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 数理科学和化学

项目作者： 吕献海

作者单位： 安徽农业大学

项目金额： 25万元

中文摘要： 水稻矮缩病毒(RDV)是水稻矮缩病的病原，目前还没有有效的防治药剂，为研发高活性抗RDV先导化合物，拟设计基于RDV关键蛋白为靶标高活性抑制剂。该研究在课题组近期发现的具有潜在抗RDV活性吡唑类化合物基础上，基于同源模建的P2蛋白模型和P3蛋白晶体结构，利用前期合成的80个新型吡唑衍生物建立训练集，参照预研发现的P2蛋白的四个关键残基SER345，ARG335，ILE268及GLY297和P3蛋白的三个关键残基ARG789，ASN934，ARG939进行多靶点药物设计及结构优化。依据分子设计的结构需要，拟以多取代4-吡唑甲醛为关键中间体进行衍生合成；对合成的目标化合物进行结构表征和抗RDV活性评价；结合活性反馈深入探讨构效关系；通过培养蛋白复合物晶体与晶体结构解析确定活性位点；以期得到更好活性的抗RDV先导化合物。通过课题的实施有助于丰富RDV抑制剂筛选的科学内涵。

中文关键词： 水稻矮缩病毒；烟草花叶病毒；吡唑衍生物；合成；靶向药物设计

英文摘要： Given the fact that there are no highly effective inhibitors for rice dwarf virus (RDV), a pathogen of rice dwarf disease, and in oredr to develop high activity lead compounds, this paper plans to design a high-activity inhibitor that takes key RDV protein as the target. Based on active pyrazole compounds with the anti - RDV property recently discovered, and on the homology modeling of the P2 and P3 protein crystal structures, it makes use of 80 novel pyrazole derivatives synthetized in an early phase to set up a training set, and conducts a multi-target design and structural optimization with the reference to four key residues of P2 protein, namely, SER345，ARG335，ILE268 and GLY297, and those of P3 protein, that is, ARG789，ASN934 and ARG939 discovered in advanced researches. According to the strcutural needs in the molecular design, it plans to use 4- pyrazole aldehyde, the polysubstutuion, as the key intermediates for the synthesis of derivatives, the structural characteristics and RDV activity assessment are to be conducted for the synthesis of the target compounds, and the structrue-activity relationship be explored in the combination with the activity feedback; in addition, the active site is to be fixed through the cultivation of protein compuound crystal and the analysis of crystal structure in an aim to

英文关键词： RDV；TMV；Pyrazole derivatives；Synthesis；Targeted drug design