目的 发现一类骨架结构新颖的聚腺苷二磷酸核糖聚合酶1（PARP1）与溴结构域蛋白4（BRD4）双靶点抑制剂。方法 从ChEMBL数据库中收集已知的BRD4抑制剂作为筛选化合物库。采用药效团与分子对接串联筛选策略，从化合物库中筛选能够和PARP1高效结合的化合物作为模板分子。对模板分子进行结构修饰，合成得到衍生物。测试衍生物对PARP1与BRD4的酶抑制活性，对乳腺癌细胞的增殖抑制能力。结果 A（化合物5l）对PARP1与BRD4有中等水平的抑制能力，对三阴性乳腺癌细胞MDA-MB-231的增殖抑制能力强于阳性药Olaparib，与JQ1水平相当。除了较高的脂水分配系数外，5l的理化性质大都分布在合理范围内，可作为先导化合物用于深入研究。结论 得到一类菲啶酮骨架结构的PARP1与BRD4双靶点抑制剂，证明通过计算机虚拟筛选发现PARP1与BRD4双靶点抑制剂是一种可行的策略。

Objective To discover a novel class of PARP1 and BRD4 dual-target inhibitors with novel scaffold structures. Methods Known BRD4 inhibitors were collected from the ChEMBL database to create a screening compound library. A combined strategy of pharmacophore modeling and molecular docking was employed to identify compounds from the library that could efficiently bind to PARP1, which were then used as template molecules for drug design. Structural modifications were made to the template molecules, resulting in the synthesis of derivatives. The inhibitory activity of these derivatives against PARP1 and BRD4 enzymes, as well as their ability to inhibit the proliferation of breast cancer cells was tested. Results A (compound 5l) exhibits moderate inhibitory activity against PARP1 and BRD4, with a stronger ability to inhibit the proliferation of triple-negative breast cancer cells MDA-MB-231 compared to the positive drug Olaparib, and at a level comparable to JQ1. Aside from a higher lipophilicity, the physicochemical properties of 5l are mostly within a reasonable range, making it a potential lead compound for further research. Conclusion A class of PARP1 and BRD4 dual-target inhibitors with a phenanthrone scaffold structure was obtained, demonstrating that computer-aided virtual screening is a feasible strategy for discovering dual-target inhibitors of PARP1 and BRD4.

R914.2

国家自然科学基金资助项目（82374050）；天津市教委科研计划项目（2021KJ126）