Ligand-Based Virtual Screening for Discovery of Indole Derivatives as Potent DNA Gyrase ATPase Inhibitors Active against Mycobacterium tuberculosis and Hit Validation by Biological Assays
Issued Date
2024-01-01
Resource Type
ISSN
15499596
eISSN
1549960X
Scopus ID
2-s2.0-85198537151
Journal Title
Journal of Chemical Information and Modeling
Rights Holder(s)
SCOPUS
Bibliographic Citation
Journal of Chemical Information and Modeling (2024)
Suggested Citation
Pakamwong B., Thongdee P., Kamsri B., Phusi N., Taveepanich S., Chayajarus K., Kamsri P., Punkvang A., Hannongbua S., Sangswan J., Suttisintong K., Sureram S., Kittakoop P., Hongmanee P., Santanirand P., Leanpolchareanchai J., Spencer J., Mulholland A.J., Pungpo P. Ligand-Based Virtual Screening for Discovery of Indole Derivatives as Potent DNA Gyrase ATPase Inhibitors Active against Mycobacterium tuberculosis and Hit Validation by Biological Assays. Journal of Chemical Information and Modeling (2024). doi:10.1021/acs.jcim.4c00511 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/99739
Title
Ligand-Based Virtual Screening for Discovery of Indole Derivatives as Potent DNA Gyrase ATPase Inhibitors Active against Mycobacterium tuberculosis and Hit Validation by Biological Assays
Author's Affiliation
Corresponding Author(s)
Other Contributor(s)
Abstract
Mycobacterium tuberculosis is the single most important global infectious disease killer and a World Health Organization critical priority pathogen for development of new antimicrobials. M. tuberculosis DNA gyrase is a validated target for anti-TB agents, but those in current use target DNA breakage-reunion, rather than the ATPase activity of the GyrB subunit. Here, virtual screening, subsequently validated by whole-cell and enzyme inhibition assays, was applied to identify candidate compounds that inhibit M. tuberculosis GyrB ATPase activity from the Specs compound library. This approach yielded six compounds: four carbazole derivatives (1, 2, 3, and 8), the benzoindole derivative 11, and the indole derivative 14. Carbazole derivatives can be considered a new scaffold for M. tuberculosis DNA gyrase ATPase inhibitors. IC50 values of compounds 8, 11, and 14 (0.26, 0.56, and 0.08 μM, respectively) for inhibition of M. tuberculosis DNA gyrase ATPase activity are 5-fold, 2-fold, and 16-fold better than the known DNA gyrase ATPase inhibitor novobiocin. MIC values of these compounds against growth of M. tuberculosis H37Ra are 25.0, 3.1, and 6.2 μg/mL, respectively, superior to novobiocin (MIC > 100.0 μg/mL). Molecular dynamics simulations of models of docked GyrB:inhibitor complexes suggest that hydrogen bond interactions with GyrB Asp79 are crucial for high-affinity binding of compounds 8, 11, and 14 to M. tuberculosis GyrB for inhibition of ATPase activity. These data demonstrate that virtual screening can identify known and new scaffolds that inhibit both M. tuberculosis DNA gyrase ATPase activity in vitro and growth of M. tuberculosis bacteria.