一种新的MDM2-p53信号通路抑制剂的发现研究
Identification of a novel MDM2-p53 interaction inhibitor using virtual screening and docking strategy
作者：涂潇(四川大学生命科学学院 生长代谢衰老中心)；李雷(四川大学生命科学学院 生长代谢衰老中心)；张海波(四川大学生命科学学院 生长代谢衰老中心)；刘扬(四川大学生命科学学院 生长代谢衰老中心)；肖智雄(四川大学生命科学学院 生长代谢衰老中心)；张渝君(四川大学生命科学学院 生长代谢衰老中心)；曹洋(四川大学生命科学学院 生长代谢衰老中心)
Author：TU Xiao(Center of Growth, Metabolism and Aging, Collage of Life Sciences, Sichuan University)；LI Lei(Center of Growth, Metabolism and Aging, Collage of Life Sciences, Sichuan University)；ZHANG Hai-Bo(Center of Growth, Metabolism and Aging, Collage of Life Sciences, Sichuan University)；LIU Yang(Center of Growth, Metabolism and Aging, Collage of Life Sciences, Sichuan University)；XIAO Zhi-Xiong(Center of Growth, Metabolism and Aging, Collage of Life Sciences, Sichuan University)；ZHANG Yu-Jun(Center of Growth, Metabolism and Aging, Collage of Life Sciences, Sichuan University)；CAO Yang(Center of Growth, Metabolism and Aging, Collage of Life Sciences, Sichuan University)
收稿日期：2018-04-09 年卷（期）页码：2019,56(2):369-376
期刊名称：四川大学学报: 自然科学版
Journal Name：Journal of Sichuan University (Natural Science Edition)
关键字：靶向治疗; p53; MDM2; 虚拟筛选
Key words：Targeted therapy; p53; MDM2; Virtual screen
基金项目：国家自然基金（31401130）
中文摘要
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.
英文摘要
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 3D 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.
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