Paving the Wayfor NLRP3 Inflammasome InactivationUsing ADAM10 and Alpha-Hemolysin: An <i>In Silico</i> Investigation

Sepsis, a life-threatening organ dysfunction driven by a dysregulated immune response, is exacerbated by excessive activation of the NLRP3 inflammasome. Alpha-hemolysin (Hla), a pore-forming toxin secreted by Staphylococcus aureus, can activate NLRP3, potentially through interactions with A Disintegrin and Metalloproteinase 10 (ADAM10). This study, therefore, aims to characterize the ADAM10–Hla interaction and its implications for NLRP3 activation, ultimately informing the development of novel, targeted therapies for sepsis. Competitive inhibition of the Hla–ADAM10 interaction by these therapies could disrupt this signaling pathway and reduce sepsis-related inflammation. The interactions between Hla and ADAM10 were analyzed using molecular docking and molecular dynamics simulations. Findings revealed favorable binding energy between Hla and ADAM10 (−43.18 kcal/mol) suggesting a mechanism by which Hla modulates ADAM10 activity and subsequently influences NLRP3 inflammasome signaling. Analysis of the root-mean-square deviation revealed that the Hla–ADAM10 complex exhibited greater conformational flexibility, the root-mean-square fluctuation revealed fluctuations between residues 175–225, which encompass key amino acids that make up the binding pockets, and the radius of gyration (RoG) revealed that the complex system had a significantly elevated RoG indicating increased overall flexibility, also suggesting that the binding of Hla to ADAM10 initiates a series of conformational changes. Lastly, amino acid residues ASN174 (−76.64 kcal/mol), ASN179 (−75.71 kcal/mol), and GLU209 (−56.17 kcal/mol) emerged as the top three major energy contributors for ADAM10. This study provides crucial structural insights into the Hla-ADAM10 interaction, highlighting its potential as a therapeutic target for sepsis treatment. Disrupting this interaction using targeted therapies, which mimic the binding domain of ADAM10, holds significant promise for mitigating the downstream inflammatory cascade. While further experimental validation through <i>in vitro</i> and <i>in vivo</i> studies is essential, this research provides a critical foundation for designing and developing innovative treatments to combat sepsis.