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(diǎn)抑制劑。方法 從ChEMBL數(shù)據(jù)庫(kù)中收集已知的BRD4抑制劑作為篩選化合物庫(kù)。采用藥效團(tuán)與分子對(duì)接串聯(lián)篩選策略，從化合物庫(kù)中篩選能夠和PARP1高效結(jié)合的化合物作為模板分子。對(duì)模板分子進(jìn)行結(jié)構(gòu)修飾，合成得到衍生物。測(cè)試衍生物對(duì)PARP1與BRD4的酶抑制活性，對(duì)乳腺癌細(xì)胞的增殖抑制能力。結(jié)果 A（化合物5l）對(duì)PARP1與BRD4有中等水平的抑制能力，對(duì)三陰性乳腺癌細(xì)胞MDA-MB-231的增殖抑制能力強(qiáng)于陽(yáng)性藥Olaparib，與JQ1水平相當(dāng)。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(dǎo)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(diǎn)抑制劑，證明通過(guò)計(jì)算機(jī)虛擬篩選發(fā)現(xiàn)PARP1與BRD4雙靶點(diǎn)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(guó)家自然科學(xué)基金資助項(xiàng)目（82374050）；天津市教委科研計(jì)劃項(xiàng)目（2021KJ126）