Virtual screening and high-throughput testing of L1 metallo-β-lactamase inhibitor  

金属-β-内酰胺酶L1抑制剂的虚拟筛选和高通量实验测试

作　　者：Chennan Liu Qian Wang Jiangxue Han Sihan Liu Chunling Xiao Yan Guan Xinghua Li Ying Wang Xiao Wang Jianzhou Meng Maoluo Gan Yishuang Liu 刘琛楠;王倩;韩江雪;刘思含;肖春玲;关艳;李兴华;王颖;王潇;蒙建州;甘茂罗;刘忆霜(中国医学科学院北京协和医学院医药生物技术研究所国家新药(微生物)筛选实验室,北京100050)

机构地区：[1]National Key Laboratory for Screening New Microbial Drugs,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China

出　　处：《Journal of Chinese Pharmaceutical Sciences》2021年第10期806-812,共7页中国药学（英文版）

基　　金：Natural Sciences Foundation of China (Grant No. 81872913);National High-tech R&D Program (863 Program, Grant No. 2015AA020911)。

摘　　要：As a zinc-dependent enzyme, metal-β-lactamase L1 contributes to the development of β-lactam antibiotic resistance. The metal-β-lactamase inhibitor can restore the efficacy of β-lactam antibiotics, and its development has attracted much attention. In the present study, we used four widely-used virtual screening programs to screen 7035 small molecules to identify potential L1 inhibitors, and a high-throughput experimental model of L1 inhibitors was established. In this high-throughput testing model, the inhibition rate of 163 compounds on L1 exceeded 40%. The results of virtual screening of 7035 small molecules using the following four programs showed that among the top 1.35% of the compounds, their hit rates were ranked as Schr?dinger’s(5.26%), DS(1.05%), and Sybyl-x 2.0(1.05%), and Smina(2.11%).金属-β-内酰胺酶L1是锌离子依赖性酶,对β-内酰胺抗生素耐药性的发展有所贡献。作为可以恢复β-内酰胺类抗生素功效的金属-β-内酰胺酶抑制剂,其研发备受关注。在本研究中,我们通过4种广泛使用的虚拟筛选程序对7035个小分子进行虚拟筛选,寻找潜在的L1抑制剂,并建立L1抑制剂的高通量实验模型。在该高通量实验模型中,163种化合物对L1的抑制率超过40%。使用下列四个程序对7035个小分子进行虚拟筛选的结果表明,在排名前1.35%的化合物里,命中率为薛定谔的(5.26%), DS (1.05%), Sybyl-x 2.0 (1.05%)和Smina (2.11%)。

关 键 词：L1 Metallo-beta-lactamase inhibitor Virtual screening High-throughput screening 

分 类 号：R962[医药卫生—药理学]