逆向合成指导的芳香化酶抑制剂全新药物设计和高通量虚拟筛选

项目名称： 逆向合成指导的芳香化酶抑制剂全新药物设计和高通量虚拟筛选

项目编号： No.21272171

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 数理科学和化学

项目作者： 张秀利

作者单位： 天津科技大学

项目金额： 80万元

中文摘要： 依据芳香化酶（CYP19）晶体结构，采用计算机全新药物设计方法设计新的芳香化酶抑制剂，产生全新结构的化合物，从而有利于发现结构新颖、活性更高和副作用更小的新药。本研究针对此方法设计出的产物许多难以合成的缺陷，采用逆向合成思想指导计算机全新药物设计，以极大地提高设计出的新化合物的可合成性，再结合2D-3D复合QSAR等模型对可合成新化合物库进行芳香化酶抑制剂的高通量虚拟筛选和计算机ADMET评价，将打分值高的化合物化学合成后进行活性测试，以获得具有自主知识产权的新一代芳香化酶抑制剂候选化合物。初步对筛选出的13个化合物进行合成和活性测试， IC50在40μg/mL以下的有8个，有活性的分子比率达到61.5%，已合成最高活性分子IC50为0.27μM，而且设计出的化合物容易合成，初步证明该方法的可行性。因此，该方法的系统实施和完善，可形成高命中率，低合成难度和成本的小分子创新药物的研究新思路。

中文关键词： 芳香化酶抑制剂；计算机辅助药物设计；虚拟筛选；构效关系；

英文摘要： Based on the crystal structure of aromatase (CYP19), the De Novo drug design method can be emploied to find the new aromatase inhbitors(Ais) with structure novelty, high potency and low side effect. However, most of the compounds generated by De Novo drug design are difficult to synthesize. In this project, the retrosynthesis theory is introduced to improve the synthesizability of the new compounds created by fragment splicing De Novo drug design. The new compounds generated with retrosynthesis theory directed De Novo drug design will then be treated with virtual screening using 2D-3D hybrid model, computer ADMET evaluation, compound synthesis and activity test to create new candidates of aromatase inhbitor. In order to verify this new drug research route, 13 compounds preliminary designed with the retrosynthesis theory directed De Novo drug design method were synthesized and their aromatase inhibit activities were determined. The results showed that ratio of the active compounds (IC50<40μg/mL) was 61.5%，and the componud with the highest aromatase inhibit activity, 0.27μM of IC50 was obtained. Thus, with the system conducting of this research, the new drug research route with high hit rate, simple to synthesized and low cost will be formed.

英文关键词： Aromatase inhibitors；Computer aided drug desigy；Virtual screening；QSAR；