金属-β-内酰胺酶L1抑制剂的虚拟筛选和高通量实验测试

doi:10.5246/jcps.2021.10.068

中国药学(英文版) ›› 2021, Vol. 30 ›› Issue (10): 806-812.DOI: 10.5246/jcps.2021.10.068

金属-β-内酰胺酶L1抑制剂的虚拟筛选和高通量实验测试

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

收稿日期:2021-05-06 修回日期:2021-05-12 接受日期:2021-06-18 出版日期:2021-10-24 发布日期:2021-10-24
通讯作者: 刘忆霜
作者简介:
+ Tel.: +86-10-63020226, E-mail: liuys@imb.pumc.edu.cn
基金资助:
Natural Sciences Foundation of China (Grant No. 81872913) and National High-tech R & D Program (863 Program, Grant No. 2015AA020911).

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

Chennan Liu, Qian Wang, Jiangxue Han, Sihan Liu, Chunling Xiao, Yan Guan, Xinghua Li, Ying Wang, Xiao Wang, Jianzhou Meng, Maoluo Gan, Yishuang Liu^*()

National Key Laboratory for Screening New Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

Received:2021-05-06 Revised:2021-05-12 Accepted:2021-06-18 Online:2021-10-24 Published:2021-10-24
Contact: Yishuang Liu

摘要/Abstract

摘要：

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, 金属-β-内酰胺酶抑制剂, 虚拟筛选, 高通量筛选

Abstract:

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%).

Key words: L1, Metallo-beta-lactamase inhibitor, Virtual screening, High-throughput screening

Supporting:

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. 金属-β-内酰胺酶L1抑制剂的虚拟筛选和高通量实验测试[J]. 中国药学(英文版), 2021, 30(10): 806-812.

Chennan Liu, Qian Wang, Jiangxue Han, Sihan Liu, Chunling Xiao, Yan Guan, Xinghua Li, Ying Wang, Xiao Wang, Jianzhou Meng, Maoluo Gan, Yishuang Liu. Virtual screening and high-throughput testing of L1 metallo-β-lactamase inhibitor[J]. Journal of Chinese Pharmaceutical Sciences, 2021, 30(10): 806-812.

图/表 9

Table 1. Top 10 compounds from DS CDOCKER.

Table 2. Top 10 compounds from Sybyl-x 2.0 virtual screening.

Table 3. Top 10 compounds from Smina virtual screening.

Table 4. Top 10 compounds from Schrodinger structure-based virtual screening.

Table 5. The parameters of the L1 testing model 1–36.

Figure 1. The five models satisfied S/B > 3, RSQ > 0.9. (a) Model 5; (b) model 11; (c) model 14; (d) model 21; (e) model 35. The model’s parameters are listed in Table 1.

Table 6. The evaluation of the L1 testing model 35.

Figure 2. A total of 7035 compounds’ IR% to L1. Inhibit ratio (IR) % = 1 – compound’s reaction speed/DMSO’s reaction speed × 100%.

Table 7. Comparison of program accuracy of L1 virtual screening.

参考文献 11

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金属-β-内酰胺酶L1抑制剂的虚拟筛选和高通量实验测试

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

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