Bioisosteric Design Identifies Inhibitors of Mycobacterium tuberculosis DNA Gyrase ATPase Activity
Issued Date
2023-05-08
Resource Type
ISSN
15499596
eISSN
1549960X
Scopus ID
2-s2.0-85154050335
Pubmed ID
37074047
Journal Title
Journal of Chemical Information and Modeling
Volume
63
Issue
9
Start Page
2707
End Page
2718
Rights Holder(s)
SCOPUS
Bibliographic Citation
Journal of Chemical Information and Modeling Vol.63 No.9 (2023) , 2707-2718
Suggested Citation
Kamsri B., Pakamwong B., Thongdee P., Phusi N., Kamsri P., Punkvang A., Ketrat S., Saparpakorn P., Hannongbua S., Sangswan J., Suttisintong K., Sureram S., Kittakoop P., Hongmanee P., Santanirand P., Leanpolchareanchai J., Goudar K.E., Spencer J., Mulholland A.J., Pungpo P. Bioisosteric Design Identifies Inhibitors of Mycobacterium tuberculosis DNA Gyrase ATPase Activity. Journal of Chemical Information and Modeling Vol.63 No.9 (2023) , 2707-2718. 2718. doi:10.1021/acs.jcim.2c01376 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/82935
Title
Bioisosteric Design Identifies Inhibitors of Mycobacterium tuberculosis DNA Gyrase ATPase Activity
Author's Affiliation
Chulabhorn Research Institute
Ramathibodi Hospital
Nakhon Phanom University
Vidyasirimedhi Institute of Science and Technology
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
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
Mutations in DNA gyrase confer resistance to fluoroquinolones, second-line antibiotics for Mycobacterium tuberculosis infections. Identification of new agents that inhibit M. tuberculosis DNA gyrase ATPase activity is one strategy to overcome this. Here, bioisosteric designs using known inhibitors as templates were employed to define novel inhibitors of M. tuberculosis DNA gyrase ATPase activity. This yielded the modified compound R3-13 with improved drug-likeness compared to the template inhibitor that acted as a promising ATPase inhibitor against M. tuberculosis DNA gyrase. Utilization of compound R3-13 as a virtual screening template, supported by subsequent biological assays, identified seven further M. tuberculosis DNA gyrase ATPase inhibitors with IC50 values in the range of 0.42-3.59 μM. The most active compound 1 showed an IC50 value of 0.42 μM, 3-fold better than the comparator ATPase inhibitor novobiocin (1.27 μM). Compound 1 showed noncytotoxicity to Caco-2 cells at concentrations up to 76-fold higher than its IC50 value. Molecular dynamics simulations followed by decomposition energy calculations identified that compound 1 occupies the binding pocket utilized by the adenosine group of the ATP analogue AMPPNP in the M. tuberculosis DNA gyrase GyrB subunit. The most prominent contribution to the binding of compound 1 to M. tuberculosis GyrB subunit is made by residue Asp79, which forms two hydrogen bonds with the OH group of this compound and also participates in the binding of AMPPNP. Compound 1 represents a potential new scaffold for further exploration and optimization as a M. tuberculosis DNA gyrase ATPase inhibitor and candidate anti-tuberculosis agent.