目的 發(fā)現(xiàn)一類骨架結(jié)構(gòu)新穎的聚腺苷二磷酸核糖聚合酶1（PARP1）與溴結(jié)構(gòu)域蛋白4（BRD4）雙靶點抑制劑。方法 從ChEMBL數(shù)據(jù)庫中收集已知的BRD4抑制劑作為篩選化合物庫。采用藥效團與分子對接串聯(lián)篩選策略，從化合物庫中篩選能夠和PARP1高效結(jié)合的化合物作為模板分子。對模板分子進行結(jié)構(gòu)修飾，合成得到衍生物。測試衍生物對PARP1與BRD4的酶抑制活性，對乳腺癌細胞的增殖抑制能力。結(jié)果 A（化合物5l）對PARP1與BRD4有中等水平的抑制能力，對三陰性乳腺癌細胞MDA-MB-231的增殖抑制能力強于陽性藥Olaparib，與JQ1水平相當。除了較高的脂水分配系數(shù)外，5l的理化性質(zhì)大都分布在合理范圍內(nèi)，可作為先導化合物用于深入研究。結(jié)論 得到一類菲啶酮骨架結(jié)構(gòu)的PARP1與BRD4雙靶點抑制劑，證明通過計算機虛擬篩選發(fā)現(xiàn)PARP1與BRD4雙靶點抑制劑是一種可行的策略。

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

國家自然科學基金資助項目（82374050）；天津市教委科研計劃項目（2021KJ126）