| 周其鈺,张娜娜,卢江溶,陈瑞,翁江,张吉泉.化学通报,2024,87(7):864-871,844. |
| PARP抑制剂的虚拟筛选、酶抑制活性及代谢稳定性研究 |
| Virtual screening, enzyme inhibitory activity and metabolic stability studies of PARP inhibitors |
| 投稿时间：2024-03-01 修订日期：2024-03-19 |
| DOI： |
| 中文关键词: PARP抑制剂 虚拟筛选 代谢稳定性 分子动力学 |
| 英文关键词:PARP inhibitors, Virtual screening, Metabolic stability, Molecular dynamics. |
| 基金项目:国家自然科学基金项目(22267003)、贵州省自然科学基金项目(黔科合基础-ZK[2023]一般305,黔科合基础-ZK[2024]一般170)和贵州省卫健委科技基金项目(gzwkj2023-511)资助 |
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| 中文摘要: |
| 聚腺苷酸二磷酸核糖聚合酶（Poly-ADP-ribose polymerase, PARP）通过“合成致死”效应对携带BRCA突变的患者疗效显著，现已成为癌症治疗的重要靶点。多款PARP抑制剂已批准上市，极大的改善了当前卵巢癌的治疗现状，但其耐药性与低亚型选择性受到了研究人员的广泛关注。本研究采用虚拟筛选和生物活性实验验证，发现化合物Y041-8647对PARP的酶抑制活性IC50 值为1.4 μM。体外代谢稳定性研究表明，Y041-8647在人工胃肠液、血浆及体外肝微粒体中稳定性良好。此外，本研究通过分子动力学揭示了Y041-8647与7KK5蛋白的相互作用模式。本研究中化合物Y041-8647可作为进一步改造的先导化合物，为新型PARP抑制剂的开发提供了新的思路。 |
| 英文摘要: |
| Poly-ADP-ribose polymerase shows significant therapeutic effect on patients bearing BRCA mutations via the "synthetic lethality" strategy, and it has become an important target in cancer treatment. Several PARP inhibitors have been approved and marketed, greatly improved the current treatment status of ovarian cancer. However, the drug resistance and low subtype selectivity have attracted great attention from researchers. In this study, the Glide docking was used for virtual screening, and the hit compound Y041-8647 was found with potent PARP inhibitory activity (PARP1, IC50: 1.4 μM) In vitro metabolic stability investigation demonstrated that Y041-8647 showed excellent stability profiles in artificial gastrointestinal fluids, plasma, and liver microsomes. Further molecular dynamics simulations elucidated the interaction patterns between Y041-8647 and the 7KK5 protein. In this research, compound Y041-8647 is identified as a lead candidate for subsequent modification, which provides novel insight into the development of novel PARP inhibitors. |
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