Identification of novel pyrazolo[4,3-c]pyridine and diazepane derivatives as potent inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase B
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Le résumé fourni par la source
ABSTRACT Tuberculosis (TB), caused by Mycobacterium tuberculosis ( M.tb ), continues to pose a critical global health threat as a leading infectious cause of mortality. Therapeutic efficacy is increasingly compromised by the emergence of multidrug-resistant strains and the limitations of existing regimens, which necessitate treatment durations of six months or longer. Protein tyrosine phosphatase B from Mtb (PtpB- Mtb ) has been recognized as a critical virulence factor, representing a promising target for novel antitubercular therapies due to its unique structural and functional properties. In this study, a comprehensive structure-based virtual screening approach was employed to identify novel small-molecule scaffolds with inhibitory potential against PtpB- Mtb . The ChemBridge compound library was curated and filtered for drug-like properties, followed by hierarchical molecular docking and molecular dynamics simulations to prioritize candidates with high predicted affinity and stability within the PtpB- Mtb active site. Quantum mechanical calculations further characterized the electronic properties of top hits. Recombinant PtpB- Mtb was expressed and purified to homogeneity, and in vitro enzymatic assays were performed to evaluate the inhibitory potency and selectivity of shortlisted compounds. Two derivatives bearing pyrazolo[4,3-c]pyridine and 1,4-diazepane ring nuclei demonstrated significant inhibition of PtpB- Mtb activity, exhibiting IC₅₀ values of 14.4 µM and 32.6 µM, respectively. Biolayer interferometry confirmed strong and specific binding to PtpB-Mtb, with dissociation constants (K d ) of 0.012 µM and 0.57 µM. The integrated workflow presented herein highlights the potential of these novel scaffolds as starting points for the development of selective, cell-permeable PtpB- Mtb inhibitors, offering a promising avenue for next-generation anti-tubercular drug discovery.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- Identification of novel pyrazolo[4,3-c]pyridine and diazepane derivatives as potent inhibitors of <i>Mycobacterium tuberculosis</i> protein tyrosine phosphatase B
- Date Crossref
- 10/03/2026
- Éditeur
- American Society for Microbiology
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Central University of Rajasthan pays non établi dans la noticeUniversité ou école supérieure
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University of Colorado Anschutz pays non établi dans la noticeUniversité ou école supérieure
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Jamia Hamdard pays non établi dans la noticeUniversité ou école supérieure
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School of Life Sciences Microbial Pathogenesis and Microbiome Lab pays non établi dans la noticeUniversité ou école supérieure
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School of Chemical Sciences and Pharmacy Department of Pharmacy pays non établi dans la noticeUniversité ou école supérieure
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University of Colorado School of Medicine Department of Immunology and Microbiology pays non établi dans la noticeUniversité ou école supérieure
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School of Chemical and Life Sciences Department of Biochemistry pays non établi dans la noticeUniversité ou école supérieure
Central University of Rajasthan, University of Colorado Anschutz et Jamia Hamdard, avec 4 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.