LPAR3选择性拮抗剂的设计、合成及抗口腔鳞状细胞癌的活性研究

项目名称： LPAR3选择性拮抗剂的设计、合成及抗口腔鳞状细胞癌的活性研究

项目编号： No.81460538

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 洪伟

作者单位： 北方民族大学

项目金额： 45万元

中文摘要： 溶血磷脂酸（LPA）能与其G蛋白偶联受体家族（LPAR1-6）结合，从而增进肿瘤细胞的增殖、存活、转移和侵袭。本团队前期研究表明，拮抗LPA与LPAR3的结合将抑制口腔鳞癌细胞的转移和侵袭，因此LPAR3有望成为治疗口腔鳞癌的新靶点。本研究将结合计算化学、药物化学、药效学等多学科交叉确定LPAR3选择性拮抗剂，并测试其抗口腔鳞癌体内外活性。课题组将借助计算机辅助药物设计和活性位点扩张这一新算法，拓展已知拮抗剂的结合位点，并且针对LPAR3与LPAR1,2的关键氨基酸电性相反这一重要特征，通过同源建模、虚拟筛选、分子对接等手段搜索分子数据库寻找LPAR3选择性拮抗剂；在此基础上通过构效关系研究、分子模拟、全新药物设计等手段进行结构优化；通过有机合成确定具有较高活性和选择性的新型LPAR3拮抗剂，并用于体外和体内抗口腔鳞癌的活性研究，预期得到1-3个候选化合物，为抗口腔鳞癌的新药研发奠定基础。

中文关键词： 计算机辅助药物设计；虚拟筛选；药物合成；抗肿瘤；分子对接

英文摘要： Lysophosphatidic acid (LPA) is a small lipid that binds to one or more members of a subfamily of G protein-coupled cell surface receptors (LPAR1-6) to trigger intracellular signalling leading to cell growth, survival and invasion and increase tumor cell movement. Our previous data showed that inhibition of LPA binding to LPAR3 can inhibit the migration and invasion of oral squamous cell carcinoma (OSCC) cells, which suggested that a strategy based on the direct targeting of LPA could lead to the development of new OSCC treatments. For this aim, we are going to use a multi-disciplinary approach using computational chemistry, medicinal chemisty and pharmcology to identify LPAR3 selective antagonists. Based on the structure and sequence analysis, the opposite charged amino acid in the binding site between LPAR3 (Lys) and LPA1/2 (Glu) was observed. This observation provides an opportunity for us to design selective antagonists for LPAR3. In the present proposal, we are going to use homology modeling, active site pressurisation (ASP),virtual screening and molecular docking etc. to identify LPAR3 selctive antagonists from the NCI and Zinc molecule databases. QSAR, molecular dynamic simulation and de novo drug design etc. will be applied to optimize the antagonists' structure, and design new compounds based on the interaction between the ligand and receptor. Newly designed compounds will be synthesized, and tested in vitro and in vivo to evaluate the biological effects on OSCC cells. Hopefully 1-3 antagonists with high activity and selectivity to LPAR3 could be identified as leading compounds for future research and the development of new drugs for the treatment of OSCC.

英文关键词： computer-aided drug design;virtual screening;organic synthesis;anti-cancer;molecular docking