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  3. Discovery of novel DprE1 inhibitors via computational bioactivity fingerprints and structure-based virtual screening

Discovery of novel DprE1 inhibitors via computational bioactivity fingerprints and structure-based virtual screening

  • Acta Pharmacol Sin. 2022 Jun;43(6):1605-1615. doi: 10.1038/s41401-021-00779-1.
Xue-Ping Hu  # 1 2,  Liu Yang  # 1,  Xin Chai 1,  Yi-Xuan Lei 1,  Md Shah Alam 3 4,  Lu Liu 5,  Chao Shen 1,  De-Jun Jiang 1,  Zhe Wang 1,  Zhi-Yong Liu 3 4,  Lei Xu 6,  Kang-Lin Wan 7,  Tian-Yu Zhang 3 4,  Yue-Lan Yin 8,  Dan Li 9,  Dong-Sheng Cao 10,  Ting-Jun Hou 11 12
Affiliations

Affiliations

  • 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.
  • 9 Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. lidancps@zju.edu.cn.
  • 10 Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, China. oriental-cds@163.com.
  • 11 Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. tingjunhou@zju.edu.cn.
  • 12 State Key Lab of CAD&CG, Zhejiang University, Hangzhou, 310058, China. tingjunhou@zju.edu.cn.
  • # Contributed equally.
PMID: 34667293 DOI: 10.1038/s41401-021-00779-1
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

DprE1; covalent inhibitors; molecular docking; tuberculosis; virtual screening.

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