Virtual Screening Identifies Novel and Potent Inhibitors of Mycobacterium tuberculosis PknB with Antibacterial Activity
Issued Date
2022-12-26
Resource Type
ISSN
15499596
eISSN
1549960X
Scopus ID
2-s2.0-85137389030
Pubmed ID
35994014
Journal Title
Journal of Chemical Information and Modeling
Volume
62
Issue
24
Start Page
6508
End Page
6518
Rights Holder(s)
SCOPUS
Bibliographic Citation
Journal of Chemical Information and Modeling Vol.62 No.24 (2022) , 6508-6518
Suggested Citation
Thongdee P., Hanwarinroj C., Pakamwong B., Kamsri P., Punkvang A., Leanpolchareanchai J., Ketrat S., Saparpakorn P., Hannongbua S., Ariyachaokun K., Suttisintong K., Sureram S., Kittakoop P., Hongmanee P., Santanirand P., Mukamolova G.V., Blood R.A., Takebayashi Y., Spencer J., Mulholland A.J., Pungpo P. Virtual Screening Identifies Novel and Potent Inhibitors of Mycobacterium tuberculosis PknB with Antibacterial Activity. Journal of Chemical Information and Modeling Vol.62 No.24 (2022) , 6508-6518. 6518. doi:10.1021/acs.jcim.2c00531 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/84025
Title
Virtual Screening Identifies Novel and Potent Inhibitors of Mycobacterium tuberculosis PknB with Antibacterial Activity
Author's Affiliation
Chulabhorn Research Institute
Ramathibodi Hospital
Nakhon Phanom University
Vidyasirimedhi Institute of Science and Technology
University of Leicester
Ubon Ratchathani University
Chulabhorn Royal Academy
Kasetsart University
University of Bristol
Thailand National Nanotechnology Center
Mahidol University
Ministry of Higher Education, Science, Research and Innovation
Ramathibodi Hospital
Nakhon Phanom University
Vidyasirimedhi Institute of Science and Technology
University of Leicester
Ubon Ratchathani University
Chulabhorn Royal Academy
Kasetsart University
University of Bristol
Thailand National Nanotechnology Center
Mahidol University
Ministry of Higher Education, Science, Research and Innovation
Other Contributor(s)
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.