盐皮质激素受体拮抗剂的虚拟筛选  

Virtual screening of antagonists for mineralocorticoid receptor

作　　者：王颖颖 刘巍[2] 孟凡翠[2] 汤立达[2] WANG Ying-ying;LIU Wei;MENG Fan-cui;TANG Li-da(Basic Medical College,Tianjin Medical University,Tianjin 300070,China;Tianjin Key Laboratory of Molecular Design and Drug Discovery,Tianjin Insitute of Pharmaceutical Research,Tianjin 300450,China)

机构地区：[1]天津医科大学基础医学院,天津300070 [2]天津药物研究院天津市新药设计与发现重点实验室,天津300450

出　　处：《中国新药杂志》2020年第6期655-661,共7页Chinese Journal of New Drugs

基　　金：天津市新药创制科技重大专项资助项目(18ZXXYSY00040)。

摘　　要：目的:采用分子对接和分子动力学方法进行盐皮质激素受体拮抗剂(mineralocorticoid receptor antagonists,MRAs)的虚拟筛选,以期发现全新结构的具有潜在治疗糖尿病肾病的先导化合物。方法:收集已知活性的MRAs及其诱饵分子,构建基于结构的盐皮质激素受体虚拟筛选模型,利用该模型对中药成分数据库(Traditional Chinese Medicines Integrated Database,TCMID)进行虚拟筛选,综合对接得分和结合模式挑选2个与阳性药类似的中药成分进行分子动力学模拟,以期发现潜在MRAs。结果:诱饵分子结果表明构建的虚拟筛选模型可用于MRAs化合物库的虚拟筛选,通过对中药成分数据库的虚拟筛选发现30个候选MRAs化合物,其中分子动力学模拟结果表明,水飞蓟莫林的结合自由能略差于已知阳性化合物,可作为MRAs的先导化合物。结论:分子对接结合分子动力学模拟方法可用于从中药成分中筛选新型盐皮质激素受体拮抗剂,为糖尿病肾病药物开发的相关实验研究提供设计思路。Objective: To obtain new potential mineralocorticoid receptor antagonists(MRAs) for treatment of diabetic nephropathy against mineralocorticoid receptor through virtual screening based on molecular docking and molecular dynamics methods. Methods: The known active MRAs compounds and their decoys were used to construct the structure based virtual screening(SBVS) model targeting MR, which was used to screen possible active compounds from Traditional Chinese Medicines Integrated Database(TCMID). Based on docking scores and binding modes, two compounds similar to the known active MRAs compounds were selected to perform further molecular dynamics simulations to obtain potential MRAs. Results: The docking results of decoys indicated that the built SBVS model was appropriate to screen MRAs. Thirty possible MRAs candidates were obtained through virtual screening of TCMID based on our SVBS model. Molecular dynamics simulation results showed that silymonin with its binding free energy slightly weaker than positive control, may be taken as a leading compound for MRAs. Conclusion: Molecular docking combined with molecular dynamics simulations can be used to screen novel MRAs from Chinese herbal medicine, providing an alternative method for discovery of MRAs for relevant experimental studies of treating diabetic nephropathy drugs.

关 键 词：盐皮质激素受体 拮抗剂 分子对接 分子动力学 虚拟筛选 

分 类 号：R914[医药卫生—药物化学]