Department of Operating Room, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China.
Chem Biol Drug Des. 2023 Oct;102(4):707-717. doi: 10.1111/cbdd.14277. Epub 2023 Jun 7.
In cancer cells, short for sirtuin (SIRT7) stabilizes the transformed state via its nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase activity. Epigenetic factor SIRT7 plays important roles in cancer biology, reversing cancer phenotypes and suppressing tumor growth when inactive. In the present study, we got the SIRT7 protein structure from Alpha Fold2 Database and performed structure-based virtual screening to develop specific SIRT7 inhibitors using the SIRT7 inhibitor 97,491 interaction mechanism. As candidates for specific SIRT7 inhibitors, compounds with high affinities to SIRT7 were chosen. ZINC000001910616 and ZINC000014708529, two of our leading compounds, showed strong interactions with SIRT7. Our MD simulation results also revealed that the 5-hydroxy-4H-thioxen-4-one group and terminal carboxyl group were critical groups responsible for interaction of small molecules with SIRT7. In our study, we demonstrated that targeting SIRT7 may offer novel therapeutic options for cancer treatment. Compounds ZINC000001910616 and ZINC000014708529 can serve as chemical probes to investigate SIRT7 biological functions and provide starting points for the development of novel therapeutics against cancers.
在癌细胞中，SIRT7（沉默调节蛋白 7）通过其烟酰胺腺嘌呤二核苷酸（NAD+）依赖性去乙酰化酶活性稳定转化状态。表观遗传因子 SIRT7 在癌症生物学中发挥着重要作用，当它不活跃时，可逆转癌症表型并抑制肿瘤生长。在本研究中，我们从 Alpha Fold2 数据库中获取了 SIRT7 蛋白结构，并使用 SIRT7 抑制剂 97,491 的相互作用机制，进行基于结构的虚拟筛选，以开发特异性 SIRT7 抑制剂。作为特异性 SIRT7 抑制剂的候选物，选择了与 SIRT7 具有高亲和力的化合物。我们的两个先导化合物 ZINC000001910616 和 ZINC000014708529 与 SIRT7 表现出强烈的相互作用。我们的 MD 模拟结果还表明，5-羟基-4H-噻吩-4-酮基团和末端羧基是小分子与 SIRT7 相互作用的关键基团。在本研究中，我们证明了靶向 SIRT7 可能为癌症治疗提供新的治疗选择。化合物 ZINC000001910616 和 ZINC000014708529 可以作为化学探针来研究 SIRT7 的生物学功能，并为开发针对癌症的新型治疗方法提供起点。
