Molecular Insights into Anabaenopeptin-Mediated Inhibition of Protein Tyrosine Phosphatase B in the <i>Mycobacterium tuberculosis</i> Complex

Among the various virulence factors produced by Mycobacterium tuberculosis, PtpB plays a critical role in regulating the M.tb pathogenesis. Genetic deletion or pharmacological inhibition of PtpB significantly impairs M.tb survival within the host, making it an attractive target for effective antitubercular therapy. Previously, Brunsvicamide B, a cyclic hexapeptide produced by the freshwater cyanobacterium Tychonema sp., was reported to inhibit the enzymatic activity of PtpB. However, the molecular details of the Brunsvicamide B–PtpB interaction remain unresolved, and elucidating this interaction could provide a structural framework for the rational design of peptide-based PtpB inhibitors. In the present study, we characterized the molecular interactions of Brunsvicamide B with PtpB, PtpA, and PstP, identifying key binding parameters responsible for the selective inhibition of PtpB. Pharmacophore models were generated for each interaction, and the complex stability was evaluated using binding energy calculations, RMSD, and RMSF analyses. Comparative analysis with the known PtpB inhibitor OMTS (PDB ID: 2OZ5) revealed that Brunsvicamide B binds to similar functional residues within the catalytic pocket of PtpB. Using the Brunsvicamide B-PtpB complex as a reference model, we screened a library of Anabaenopeptins for their ability to inhibit PtpB and its homologues across the members of the M. tuberculosis complex. This approach led to the identification of three candidate peptides exhibiting favorable safety, bioavailability, and excretion profiles compared to OMTS. Thus, the shortlisted Anabaenopeptins represent promising leads for the development of pan-MTBC PtpB inhibitors with potential application in next-generation TB therapeutics.