2. Academic Validation
  3. Virtual Screening Identifies Novel and Potent Inhibitors of Mycobacterium tuberculosis PknB with Antibacterial Activity

Virtual Screening Identifies Novel and Potent Inhibitors of Mycobacterium tuberculosis PknB with Antibacterial Activity

  • J Chem Inf Model. 2022 Aug 22. doi: 10.1021/acs.jcim.2c00531.
Paptawan Thongdee 1,  Chayanin Hanwarinroj 1,  Bongkochawan Pakamwong 1,  Pharit Kamsri 2,  Auradee Punkvang 2,  Jiraporn Leanpolchareanchai 3,  Sombat Ketrat 4,  Patchreenart Saparpakorn 5,  Supa Hannongbua 5,  Kanchiyaphat Ariyachaokun 6,  Khomson Suttisintong 7,  Sanya Sureram 8,  Prasat Kittakoop 8 9 10,  Poonpilas Hongmanee 11,  Pitak Santanirand 11,  Galina V Mukamolova 12,  Rosemary A Blood 13,  Yuiko Takebayashi 13,  James Spencer 13,  Adrian J Mulholland 14,  Pornpan Pungpo 1
Affiliations

Affiliations

  • 1 Department of Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani, 34190, Thailand.
  • 2 Division of Chemistry, Faculty of Science, Nakhon Phanom University, Nakhon Phanom, 48000, Thailand.
  • 3 Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, 10400, Thailand.
  • 4 School of Information Science and Technology, Vidyasirimedhi Institute of Science and Technology, Rayong, 21210, Thailand.
  • 5 Department of Chemistry, Faculty of Science, Kasetsart University, Bangkok, 10900, Thailand.
  • 6 Department of Biological Science, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani, 34190, Thailand.
  • 7 National Nanotechnology Center, NSTDA, 111 Thailand Science Park, Klong Luang, Pathum Thani, 12120, Thailand.
  • 8 Chulabhorn Research Institute, Bangkok, 10210, Thailand.
  • 9 Chulabhorn Graduate Institute, Chemical Biology Program, Chulabhorn Royal Academy, Bangkok, 10210, Thailand.
  • 10 Center of Excellence on Environmental Health and Toxicology (EHT), OPS, Ministry of Higher Education, Science, Research and Innovation, Bangkok, 10210, Thailand.
  • 11 Division of Microbiology, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand.
  • 12 Leicester Tuberculosis Research Group, Department of Respiratory Sciences, University of Leicester, Maurice Shock Medical Sciences Building, University Road, Leicester, LE1 9HN, United Kingdom.
  • 13 School of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, Bristol, BS8 1TD, United Kingdom.
  • 14 Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol, BS8 1TS, United Kingdom.
PMID: 35994014 DOI: 10.1021/acs.jcim.2c00531
Abstract

Mycobacterium tuberculosis protein kinase B (PknB) is essential to mycobacterial growth and has received considerable attention as an attractive target for novel anti-tuberculosis drug development. Here, virtual screening, validated by biological assays, was applied to select candidate inhibitors of M. tuberculosis PknB from the Specs compound library (www.specs.net). Fifteen compounds were identified as hits and selected for in vitro biological assays, of which three indoles (2, AE-848/42799159; 4, AH-262/34335013; 10, AP-124/40904362) inhibited growth of M. tuberculosis H37Rv with minimal inhibitory concentrations of 6.2, 12.5, and 6.2 μg/mL, respectively. Two compounds, 2 and 10, inhibited M. tuberculosis PknB activity in vitro, with IC50 values of 14.4 and 12.1 μM, respectively, suggesting this to be the likely basis of their anti-tubercular activity. In contrast, compound 4 displayed anti-tuberculosis activity against M. tuberculosis H37Rv but showed no inhibition of PknB activity (IC50 > 128 μM). We hypothesize that hydrolysis of its ethyl ester to a carboxylate moiety generates an active species that inhibits other M. tuberculosis enzymes. Molecular dynamics simulations of modeled complexes of compounds 2, 4, and 10 bound to M. tuberculosis PknB indicated that compound 4 has a lower affinity for M. tuberculosis PknB than compounds 2 and 10, as evidenced by higher calculated binding free energies, consistent with experiment. Compounds 2 and 10 therefore represent candidate inhibitors of M. tuberculosis PknB that provide attractive starting templates for optimization as anti-tubercular agents.

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