EXPLORING ADAM10 AS A DRUG TARGET: MOLECULAR DOCKING ANALYSIS FOR ALZHEIMER’S DISEASE DRUG REPURPOSING

Abstract

Aim: AD (Alzheimer’s disease) is a chronic and irreversible brain disease identified by cognitive decline, memory loss, and behavioural anomalies. A major pathological characteristic of AD is abnormal accumulation of Aβ plaques, resulting from the improper breaking of APP. Among the critical enzymes involved in APP processing, ADAM10 (A Dis-integrin and Metalloprotease 10) plays a pivotal role as an α-secretase, promoting the non-amyloidogenic pathway and preventing the formation of toxic Aβ peptides. Increasing the action of ADAM10 has therefore emerged as a promising therapeutic approach in the management of AD. The present study focused on identifying potential modulators of ADAM10, a critical healing target implicated in AD, through a molecular docking-based drug repurposing approach. Drugs structurally similar with Donepezil, a known enhancer of ADAM10 identified using computational screening tools. To develop more effective treatment strategies for Alzheimer's disease, the study intends to use molecular docking to find alternative or repurposed therapeutics that might offer better binding affinity and possibly better therapeutic outcomes than donepezil. Results: Docking simulations revealed that several compounds demonstrated higher binding affinities compared to Donepezil, indicating stronger potential interactions with ADAM10's active site. Notably, several drugs exhibited higher binding affinities than Donepezil, suggesting stronger and potentially more effective interactions with ADAM10. Among these, Ziprasidone, Oxatomide, Metergoline, Lasmiditan, and Domperidone emerged as the most promising candidates, demonstrating superior docking scores and favourable interaction profiles. Further, 2D interaction analysis was carried out using BIOVIA Discovery Studio, which visually illustrated key binding interactions such as hydrogen bonds, hydrophobic interactions, and π–π stacking between the ligands and critical amino acid residues of the ADAM10 protein followed by a toxicity assessment using ProTox II server. Conclusion: The binding affinity result, interaction profiles and toxicity analysis strongly suggest that certain FDA-approved drugs could serve as promising candidates for repurposing as ADAM10 modulators in AD therapy. These studies provide the scope for future in vitro and in vivo validations to confirm their remedial capabilities.