Zinc-Facilitated Enzyme Disruption: Thiazolidinediones as Potent Carbonic Anhydrase Inhibitors in Hypoxic Cancer Microenvironments.

INTRODUCTION

Thiazolidinedione (TZD) derivatives have gained significant attention as anti-cancer agents due to their diverse biological activities. The objective of the research was to investigate the potential of thiazolidine derivatives as inhibitors of Carbonic anhydrase XII, an isoform overexpressed in hypoxic tumor environments, to explore their application as anticancer agents targeting breast cancer.

METHODS

The study employed a computational approach to evaluate thiazolidine derivatives as potential CA XII inhibitors. Acute toxicity and safety were evaluated using ProTox 3.0. Molecular docking was conducted to study interactions with the zinc-bound active site of CA XII. Molecular dynamics simulations were performed to validate the stability of the ligand-enzyme complex over 250 ns.

RESULTS

TZD derivatives demonstrated favorable physicochemical properties, high gastrointestinal absorption, and low toxicity risks. Molecular docking studies showed strong binding affinities with key hydrogen bonding and zinc coordination at the CA XII active site. Toxicity predictions indicated that most compounds had acceptable safety margins, reinforcing their potential as safe and effective CA XII inhibitors.

DISCUSSION: The findings suggest that thiazolidine scaffolds could serve as promising small-molecule inhibitors of CA XII by targeting its zinc-bound catalytic site, a mechanism consistent with previously reported CA inhibitor pharmacology.

CONCLUSION

The study demonstrates that TZD derivatives possess promising characteristics as CA XII inhibitors, with favorable physicochemical properties, strong binding affinity, stable ligand-protein interactions, and acceptable safety profiles. These findings highlight their potential for further in vitro and in vivo validation, supporting the continued exploration of thiazolidinedione scaffolds in the development of targeted anticancer therapies.