Protein arginine methyltransferase 5 (PRMT5) is an epigenetics related enzyme that has been validated as an important therapeutic target for glioblastoma and mantel cell lymphoma. In the present study, 11 novel PRMT5 inhibitors with 5-benzylidene-2-phenylthiazolone scaffold were identified by molecular docking-based virtual screening and structural optimization. Their IC₅₀ values against PRMT5 at enzymatic level were ranging from 0.77 to 23 μM. As expected, the top two active hits (5 and 19) showed potent anti-proliferative activity against MV4-11 cells with EC₅₀ values lower than 10 μM and reduced the cellular symmetric arginine dimethylation levels of SmD3 protein. Besides, 5 and 19 demonstrated the mechanism of cell killing in cell cycle arrest and apoptotic effect. The probable binding modes of the two compounds were explored and further verified by molecular dynamics simulation. The structure-activity relationship (SAR) of this class of structures was also discussed and further demonstrated by molecular docking simulation.

蛋白质精氨酸甲基转移酶5（PRMT5）是一种表观遗传学相关的酶，已被证实是胶质母细胞瘤和壁炉细胞淋巴瘤的重要治疗靶标。在本研究中，通过基于分子对接的虚拟筛选和结构优化，鉴定了11种新颖的具有5-亚苄基-2-苯基噻唑酮骨架的PRMT5抑制剂。在酶促水平下，它们针对PRMT5的IC ₅₀值为0.77至23μM。如预期的那样，前两个有效命中位点（5和19）显示出对MV4-11细胞的有效抗增殖活性，其EC ₅₀值低于10μM，并降低了SmD3蛋白的细胞对称精氨酸二甲基化水平。此外5和19在细胞周期停滞和凋亡效应中证明了细胞杀伤的机制。探索了这两种化合物的可能结合方式，并通过分子动力学模拟进一步验证了它们的结合方式。还讨论了此类结构的结构-活性关系（SAR），并通过分子对接模拟进一步证明了这一关系。