Preliminary study on high throughput screening small molecules targeting Gram-negative bacilli outer membrane protein BamA
10.3760/cma.j.cn114452-20221114-00678
- VernacularTitle:高通量筛选靶向革兰阴性菌BamA蛋白的小分子药物初步研究
- Author:
Pengfei SHE
1
;
Zehao LI
;
Shasha LIU
;
Yimin LI
;
Linhui LI
;
Yifan YANG
;
Linying ZHOU
;
Yong WU
Author Information
1. 中南大学湘雅三医院检验科，长沙 410013
- Keywords:
Small molecule libraries;
Bacterial outer membrane protein;
Drug synergism;
Acinetobacter baumannii;
High-throughput screening assay
- From:
Chinese Journal of Laboratory Medicine
2023;46(6):597-603
- CountryChina
- Language:Chinese
-
Abstract:
Objective:High-throughput screening to obtain small molecular compounds against Gram-negative bacilli by targeting BamA outer membrane protein.Methods:The sybyl-X2.1 software was used to perform high-throughput virtual screening of small molecular compounds in Chemdiv compound library based on the molecular docking. The top 150 hits by high-throughput screening were re-screened through in vitro biological experiments. The top 4 small molecules with obvious antibacterial activity were selected for in-depth molecular docking analysis, and the small molecule 8308-0401 with the highest docking score was selected for further experiments. The antibacterial effect of 8308-0401 combined with rifampicin was tested by checkerboard assay. Finally, the affinity between 8308-0401 and BamA was tested by plasma surface resonance assay. Results:The docking score of the top 150 hits calculated by high-throughput virtual screening had a mean value of 5.63. In vitro biological experiments showed that small molecules 8308-0401, 8365-1335, C066-2507 and L582-0346 exhibited strong antibacterial activity. Among those molecules, 8308-0401 showed the highest molecular docking score, and synergistic antibacterial activity against both types of strains and clinical isolates when combined with rifampicin. 8308-0401 has a strong affinity to BamA with binding a constant of 182 μmol/L. Conclusion:The small molecule 8308-0401 exerts antibacterial activity against Gram negative bacilli by targeting the outer membrane protein BamA.
