【摘要】 本研究以研发新型小分子MDM2抑制剂为目的,建立了以分子对接为基础的虚拟筛选流程.利用虚拟筛选流程对SPECS化合物库的分子进行类药性筛选、分子对接粗筛、二次筛选以及排序挑选,并通过细胞实验验证这些分子激活p53并抑制肿瘤细胞生长的活性.结果表明M12能够激活p53及其下游信号通路,抑制肿瘤细胞周期并促进肿瘤细胞凋亡.M12与已知MDM2-p53抑制剂结构完全不同,是一种潜在的癌症治疗候选药物.更多还原

【Abstract】 In this study we employed a docking approach based on virtual screening to search for inhibitors that can bind to MDM2 and block MDM2-p53 interaction. Candidate compounds were obtained from SPECS library. We processed two rounds of molecular docking. Putative compounds were selected based on binding score ranking and 3 D structure inspection. Furthermore, the selected small molecules were validated by cell-based experiments. Treatment of several cancer cells with M12 led to activating p53, and upregulation of p21, leading to cell cycle arrest and apoptosis. To this end, we discovered a novel small molecule named M12 that is structurally different from the known MDM2 antagonists, M12 may be a novel small compound and a potentially useful drug candidate for cancer treatment.更多还原