Hybrid virtual screening identifies dipyrazole carboxamide derivatives as novel direct InhA inhibitors with antitubercular activity
6
Issued Date
2025-07-01
Resource Type
ISSN
03044165
eISSN
18728006
Scopus ID
2-s2.0-105006581436
Journal Title
Biochimica Et Biophysica Acta General Subjects
Volume
1869
Issue
8
Rights Holder(s)
SCOPUS
Bibliographic Citation
Biochimica Et Biophysica Acta General Subjects Vol.1869 No.8 (2025)
Suggested Citation
Punkvang A., Pakamwong B., Phusi N., Thongdee P., Chayajarus K., Sangswan J., Pangjit K., Suttisintong K., Leanpolchareanchai J., Hongmanee P., Santanirand P., Spencer J., Mulholland A.J., Sureram S., Kittakoop P., Pungpo P. Hybrid virtual screening identifies dipyrazole carboxamide derivatives as novel direct InhA inhibitors with antitubercular activity. Biochimica Et Biophysica Acta General Subjects Vol.1869 No.8 (2025). doi:10.1016/j.bbagen.2025.130827 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/110460
Title
Hybrid virtual screening identifies dipyrazole carboxamide derivatives as novel direct InhA inhibitors with antitubercular activity
Corresponding Author(s)
Other Contributor(s)
Abstract
Direct inhibitors of M. tuberculosis enoyl-acyl carrier protein reductase (M. tuberculosis InhA) remain effective against variants with mutations associated with isoniazid resistance. In our previous study, structure-based virtual screening was employed to discover such inhibitors. However, most identified hits exhibited limited antimycobacterial activity, with minimum inhibitory concentration (MIC) values of >100 μg/mL. To address this challenge, we refined our virtual screening strategy by integrating ligand- and structure-based virtual screening approaches. The efficacy of this hybrid virtual screening approach was validated through biological assays measuring MIC and half-maximal inhibitory concentration (IC<inf>50</inf>) for the inhibition of M. tuberculosis growth and InhA activity, respectively. Among 14 identified hits, compounds 3 and 10, classified as dipyrazole carboxamide derivatives, were validated as promising lead candidates, with MIC values of 25 and 50 μg/mL and IC<inf>50</inf> values of 10.60 ± 0.56 and 5.08 ± 0.30 μM, respectively. The relatively low hit-to‑lead conversion rate (14 %) is ascribed to our observation that nine of the identified hits, including compounds 3 and 10, showed some level of precipitation in the MIC assay medium. Molecular dynamics simulations show that the dipyrazole carboxamide moiety in compounds 3 and 10 forms essential hydrogen bonds with nicotinamide adenine dinucleotide (oxidized form) (NAD<sup>+</sup>) in the InhA binding pocket. Notably, both compounds 3 and 10 exhibit favorable safety profiles, with no toxicity observed in Caco-2 cells at concentrations up to 100 μg/mL. Consequently, we believe that these compounds present promising starting points for further lead optimization and development of novel antitubercular agents.