| 王廷良,张娜娜,翁江,张吉泉.化学通报,2023,86(9):1137-1145. |
| 基于结构虚拟筛选发现PRMT5抑制剂 |
| Discovery of PRMT5 Inhibitors via Structure-based Virtual Screening |
| 投稿时间：2022-12-02 修订日期：2023-02-16 |
| DOI： |
| 中文关键词: PRMT5抑制剂 虚拟筛选 分子对接 分子动力学 |
| 英文关键词:PRMT5 inhibitor, Virtual screening, Molecular docking, Molecular dynamics |
| 基金项目:国家自然科学基金项目(22267003,82060625)和贵州医科大学优秀青年人才计划项目[(2022)102]资助 |
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| 中文摘要: |
| 蛋白质精氨酸甲基转移酶5(PRMT5)是蛋白质甲基转移酶家族(PRMTs)的重要一员,其主要生理功能是催化精氨酸单对称二甲基化。PRMT5的上调发生在不同类型的肿瘤中,并与不良预后密切相关,已被视为肿瘤治疗中的潜在靶点。近年来,已有多种PRMT5抑制剂进入临床试验,但目前尚未有药物获批上市。本研究基于Glide对接的虚拟筛选和生物活性实验,发现化合物8018-1271对PRMT5酶的抑制活性IC50值为13.56 ± 0.86 μM,并通过分子动力学揭示其与PRMT5蛋白结构域的相互作用模式。本研究所得化合物8018-1271可作为进一步改造的先导化合物,为新型PRMT5抑制剂发现奠定了基础。 |
| 英文摘要: |
| Protein arginine methyltransferases 5 (PRMT5) is one of the important members of the protein methyltransferases family (PRMTs), which catalyzes the asymmetric dimethylation of arginine. The up regulation of PRMT5 occurs in different types of tumors and is closely related to their poor prognosis. PRMT5 has been considered as a potential target in tumor therapy. In recent years, many PRMT5 inhibitors have advanced into clinical trials, but no drugs have been approved for marketing. In this work, Glide docking-based virtual screening and subsequent biological evaluation were performed, and the novel PRMT5 inhibitor 8018-1271 was found with an inhibitory IC50 value of 13.56 ± 0.86 μM. The potential molecular interaction mode of 8018-1271 with PRMT5 protein domain has been investigated by molecular dynamics. Compound 8018-1271 could be used as a lead compound for the development of novel PRMT5 inhibitors. |
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