Colchicine as inhibitor of caspase-1 and GSTO-1 to regulate inflammation-induced pyroptosis in ischemic heart disease: A computational investigation

Context: Inflammation-induced pyroptosis amplification contributes to the deterioration of ischemic heart diseases (IHD). Triggered by inflammasome activation, it provokes inflammatory reactions involving proteins such as glutathione transferase omega-1 (GSTO-1), NLRP-3 inflammasome, and caspase-1 (CASP-1), which might be prevented by colchicine. However, the mechanism remains to be explored. Aims: To explore colchicine's potential to inhibit CASP-1, GSTO-1, and NLRP-3 to alleviate pyroptosis by mean computational methods. Methods: Structures of colchicine, CASP-1, GSTO1-1, and NLRP3 were obtained from databases, followed by molecular docking and dynamics simulations to evaluate colchicine's inhibitory potential. NSC697923 and KT53 were used as reference compounds to validate the docking and molecular dynamics analyses. Results: Molecular docking showed that colchicine binds to CASP-1 and GSTO-1 with lower binding energy than their native ligands, indicating strong inhibitory potential. Molecular dynamics simulations further confirmed that colchicine forms stable and robust interactions with CASP-1 and GSTO-1, supporting its effectiveness as an inhibitor. In contrast, colchicine’s interaction with NLRP-3 was less stable, suggesting a lower inhibitory potential. Comparative analysis with NSC697923 and KT53, potent inhibitors of CASP-1 and GSTO-1, respectively, reinforced colchicine’s stable conformation and sufficient hydrogen bonds despite its slightly higher binding affinity, underscoring its sustained interaction with CASP-1 and GSTO-1. Conclusions: Colchicine showed a promising inhibitory potential agent against CASP-1 and GSTO-1, highlighting its potential for regulating inflammation in IHD. The stable binding of colchicine to CASP-1 and GSTO-1 indicated a potential inhibitory mechanism against inflammation-induced pyroptosis in IHD.