Computational Analysis of Zn ²⁺ Mediated Non-Competitive Inhibition to Caspase-3

Caspase-3, a critical mediator of apoptosis, is implicated in neurodegenerative diseases and cancer, making it an attractive therapeutic target. Here, we elucidated the molecular mechanisms of caspase-3 inhibition through computational methods. We first investigated the binding of the canonical substrate DEVD and novel peptidomimetic inhibitors, characterizing their competitive inhibition mechanisms. Using AlphaFold3 and molecular dynamics simulations, we then identify Zn ²⁺ -binding sites and characterize conformational changes induced by Zn ²⁺ chelation, revealing a mechanism for non-competitive inhibition. Our results provide atomic-level insights into both competitive and Zn ²⁺ -mediated non-competitive inhibition of caspase-3, enhancing our understanding of apoptotic pathways. These findings could help guide the development of targeted therapies for apoptosis-related disorders, encompassing both competitive inhibitors and non-competitive modulators.