基于FDA批准药物数据的新型胆碱酯酶抑制剂发现  

Discovery of New Cholinesterase Inhibitors Based on the Database of FDA-Approved Drugs

作　　者：周游[1] 薛鑫[2] 王磊[3] 孙昊鹏[3] ZHOU You;XUE Xin;Wang Lei;SUN Haopeng(College of Sericulture,Textile and Biomass Sciences,Southwest University,Chongqing 400715,China;School of Pharmacy,Nanjing University of Chinese Medicine,Nanjing 210023,China;School of Pharmacy,China Pharmaceutical University,Nanjing 211198,China)

机构地区：[1]西南大学蚕桑纺织与生物质科学学院,重庆400715 [2]南京中医药大学药学院,南京210023 [3]中国药科大学药学院,南京211198

出　　处：《西南大学学报（自然科学版）》2022年第12期60-69,共10页Journal of Southwest University(Natural Science Edition)

基　　金：国家自然科学基金青年基金项目(81803367).

摘　　要：以中枢胆碱能假说为基础设计的胆碱酯酶抑制剂仍然是阿尔茨海默症临床治疗的首选策略之一,目前仅有4个胆碱酯酶抑制剂进入临床,因此新型胆碱酯酶抑制剂的发现十分迫切.首先以药效团模型与分子对接,对美国食品药品监督管理局(FDA)批准药物库进行虚拟筛选,4个药物(米托蒽醌、帕比司他、赖诺普利、赖斯丹明)被识别作为潜在的胆碱酯酶抑制剂.基于血脑屏障渗透性预测与可获得性,3个药物被购买进行体外活性验证.结果显示:抗肿瘤药物米托蒽醌具有有效的乙酰胆碱酯酶抑制活性(IC_(50)=0.85μmol/L)以及丁酰胆碱酯酶抑制活性(IC_(50)=6.45μmol/L).考虑到上市药物具有适宜的理化性质及良好的安全性,研究为接下来设计高活性、高成药性胆碱酯酶抑制剂提供了理想的研究起点.Cholinesterase inhibitors represent one of the most effective therapeutic strategies for the treatment of Alzheimer s disease(AD).Considering only four cholinesterase inhibitors have been released to the market,it is an urgent task to identify novel cholinesterase inhibitors.In the study,pharmacophore-bosed virtual screening and molecular docking were performed using the FDA-opproved drug library.Four drugs(mitoxantrone,panobinostat,lisinopril,lisdexamfetamine)were identified as potential cholinesterase inhibitors.Based on the predicted blood-brain barrier(BBB)permeability and availability,three of them were purchased for activity verification.Among them,mitoxantrone showed potent in vitro inhibitory activity against both acetylcholinesterase(IC_(50)=0.85μmol/L)and butylcholinesterase(IC_(50)=6.45μmol/L).Considering that approved drugs have satisfied physicochemical properties and safety,the present study provided us with a good starting point to further design highly potent cholinesterase inhibitors with novel scaffold and proper drug-like property.

关 键 词：阿尔茨海默症 胆碱酯酶 虚拟筛选 米托蒽醌 

分 类 号：Q503[生物学—生物化学] R914[医药卫生—药物化学]