RT Journal Article SR Electronic T1 Computational Analysis of Zn2+ Mediated Non-Competitive Inhibition to Caspase-3 JF bioRxiv FD Cold Spring Harbor Laboratory SP 2024.09.30.615770 DO 10.1101/2024.09.30.615770 A1 Tian, Xinyu Erya A1 Zang, Min A1 Wang, Xiaoyu A1 Dong, Hao YR 2024 UL http://biorxiv.org/content/early/2024/10/01/2024.09.30.615770.abstract AB 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 Zn2+-binding sites and characterize conformational changes induced by Zn2+ chelation, revealing a mechanism for non-competitive inhibition. Our results provide atomic-level insights into both competitive and Zn2+-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.Competing Interest StatementThe authors have declared no competing interest.