Discovery of novel DprE1 inhibitors via computational bioactivity fingerprints and structure-based virtual screening
Xue-ping Hu1,2,
Liu Yang1,
Xin Chai1,
Yi-xuan Lei1,
Md Shah Alam3,4,
Lu Liu5,
Chao Shen1,
De-jun Jiang1,
Zhe Wang1,
Zhi-yong Liu3,4,
Lei Xu6,
Kang-lin Wan7,
Tian-yu Zhang3,4,
Yue-lan Yin8,
Dan Li1,
Dong-sheng Cao5,
Ting-jun Hou1,2
1 Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
2 State Key Lab of CAD&CG, Zhejiang University, Hangzhou 310058, China
3 State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
4 University of Chinese Academy of Sciences, Beijing 100049, China
5 Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
6 Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou 213001, China
7 State Key Laboratory of Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China
8 Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou 225009, China
Correspondence to: Dan Li: lidancps@zju.edu.cn, Dong-sheng Cao: oriental-cds@163.com, Ting-jun Hou: tingjunhou@zju.edu.cn,
DOI: 10.1038/s41401-021-00779-1
Received: 28 July 2021
Accepted: 16 September 2021
Advance online: 19 October 2021
Abstract
Decaprenylphosphoryl-β-D-ribose oxidase (DprE1) plays important roles in the biosynthesis of mycobacterium cell wall. DprE1 inhibitors have shown great potentials in the development of new regimens for tuberculosis (TB) treatment. In this study, an integrated molecular modeling strategy, which combined computational bioactivity fingerprints and structure-based virtual screening, was employed to identify potential DprE1 inhibitors. Two lead compounds (B2 and H3) that could inhibit DprE1 and thus kill Mycobacterium smegmatis in vitro were identified. Moreover, compound H3 showed potent inhibitory activity against Mycobacterium tuberculosis in vitro (MICMtb = 1.25 μM) and low cytotoxicity against mouse embryo fibroblast NIH-3T3 cells. Our research provided an effective strategy to discover novel anti-TB lead compounds.
Keywords:
molecular docking; virtual screening; DprE1; tuberculosis; covalent inhibitors
