Targeting the ADAM10-Alpha Hemolysin Axis Using Ascorbyl Stearate as a Potential Therapy in S. aureus Infections: In...

A disintegrin and metalloproteinase 10 (ADAM10)-alpha hemolysin (AHL) axis plays a role in S. aureus infections. Thus, ADAM10-AHL interaction is of great interest in research of targeted therapeutics such as ADAM10 inhibitors and AHL toxin decoys. The ADAM10-AHL pathway has been leveraged to design host-targeted therapy for S. aureus infection treatment, with ADAM10 inhibitors and toxin decoys showing potential. Therefore, there is a need to widen the pool of new ADAM10 inhibitors and AHL toxin decoys. In this regard, for the first time, we assess the potential of l-ascorbyl 6-stearate (AS) to bind to ADAM10 and AHL. AS, being amphiphilic, can interact with AHL and ADAM10 to modulate their activities. However, this interaction remains to be experimentally tested. To understand this interaction, we assessed the binding of AS to ADAM10 and AHL via molecular docking, MD simulation, and microscale thermophoresis (MST) techniques. Molecular docking revealed the key binding residues in ADAM10 and AHL, while MD simulation showed AS-induced conformational changes with increased protein stability. The MST confirmed the interaction of AS with ADAM10 and AHL with favorable K _d values of 24.442 μM and 2.9985 μM, respectively. These useful insights into the interactions of AS with ADAM10 and AHL would guide development of potential therapies for S. aureus infections.