{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:13:46Z","timestamp":1785428026901,"version":"3.56.0"},"reference-count":61,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Infect Immun"],"published-print":{"date-parts":[[2026,3,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Tuberculosis (TB), caused by\n                      <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">M.tb<\/jats:italic>\n                      ), 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\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      (PtpB-\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      ) 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-\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      . 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-\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      active site. Quantum mechanical calculations further characterized the electronic properties of top hits. Recombinant PtpB-\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      was expressed and purified to homogeneity, and\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      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-\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      activity, exhibiting IC\u2085\u2080 values of 14.4 \u00b5M and 32.6 \u00b5M, respectively. Biolayer interferometry confirmed strong and specific binding to PtpB-Mtb, with dissociation constants (K\n                      <jats:sub>d<\/jats:sub>\n                      ) of 0.012 \u00b5M and 0.57 \u00b5M. The integrated workflow presented herein highlights the potential of these novel scaffolds as starting points for the development of selective, cell-permeable PtpB-\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      inhibitors, offering a promising avenue for next-generation anti-tubercular drug discovery.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/iai.00738-25","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T15:24:22Z","timestamp":1770650662000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Identification of novel pyrazolo[4,3-c]pyridine and diazepane derivatives as potent inhibitors of\n                    <i>Mycobacterium tuberculosis<\/i>\n                    protein tyrosine phosphatase 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