Employing Multifaceted Bioinformatics Strategies for the Discovery of Novel ASK1 Inhibitors Targeting Neurodegenerative Disorders

Neurodegenerative diseases, characterized by reactive oxygen species-induced oxidative perturbation, ER stress, intracellular stress, and inflammation, often lead to neuronal cellular toxicity and death. The MAP3K ASK1 plays a pivotal role in this process, mediating the downstream activation of MAP2K and MAP1K family proteins. Given its involvement in various neurodegenerative diseases and cancer, ASK1 emerges as a promising therapeutic target. To identify potential inhibitors, a comprehensive approach was undertaken. Docking simulations involving 3,674 FDA-approved drugs were conducted, aiming to discover compounds with superior affinity compared to existing drugs. This extensive screening process narrowed down the candidates, and subsequent SWISS-ADME analysis was performed to evaluate the physicochemical properties, bioavailability, solubility, and lipophilicity of the selected ligands. Among the examined drugs, one emerged as a particularly promising candidate for targeting ASK1. The selection was based not only on its binding affinity but also on favorable physicochemical characteristics crucial for drug development. This robust methodology combines molecular docking, leveraging the vast library of FDA-approved drugs, with advanced ADME analysis, enhancing the likelihood of identifying a drug with therapeutic potential. This integrated approach holds promise in uncovering novel ASK1 inhibitors, providing a foundation for further preclinical and clinical investigations. The identified candidate exhibits strong potential for therapeutic intervention in neurodegenerative disorders, offering new avenues for drug development and treatment strategies.