Systematic modeling of porphyrin-based photosensitizers for inhibiting Mycobacterium tuberculosis β-Carbonic Anhydrases

Mycobacterium tuberculosis β-carbonic anhydrases (Mtb-CAs) are zinc-dependent enzymes that play a role in intracellular pH regulation and bacterial physiology within the host. This is because these enzymes are involved in adaptation under hostile conditions, they represent potential molecular targets for anti-tuberculosis research, particularly in the context of drug-resistant strains. In this study, two zinc(II) porphyrin derivatives, AMA01127 and AMA02194, initially designed for anticancer photodynamic therapy, were evaluated for their ability to inhibit the three β-class carbonic anhydrases of Mtb (β-CA1-3) and to explore associated host-pathogen network relationships. Enzymatic assays revealed that AMA02194 selectively inhibited Mtb-CAβ1 and β2 with inhibition constants of 8.2 and 39.7 nM, respectively, and displayed stronger potency than the reference inhibitor acetazolamide under the tested conditions. Docking analyses supported these findings by showing favorable binding of AMA02194 to the zinc-coordinated active site of β-CA1 and β-CA2, stabilized through hydrophobic and polar interactions. AMA01127 demonstrated the strongest docking affinity toward β-CA1 but exhibited comparatively weaker inhibition across isoforms. Network-based systems analysis identified enrichment of biological processes associated with zinc ion binding, peptidase activity, and lipid metabolism. Host gene expression profiling provided a lung-tissue expression context and computationally predicted associations for genes including CTSD, GSTP1, and NFE2L2, which are annotated to immune and redox-related functions. Overall, the results support AMA02194 as an isoform-selective inhibitor of Mtb β-carbonic anhydrases at the enzyme level and provide a computational framework for further investigation of porphyrin-based modulators in tuberculosis-related studies.