INNOVATIVE THERAPEUTICS FOR NEURODEGENERATIVE DISEASES : COMPUTATIONAL IDENTIFICATION OF ASK1 INHIBITORS FROM DIVERSE COMPOUND LIBRARIES

Abstract

ND characterized by the loss of essential neurons, affects around 50 million people globally, with numbers expected to triple by 2050. AD is the most common ND, predominantly affecting women, followed by Parkinson's disease. In ND, Aging, and genetics are major contributors. Misfolded protein aggregation and oxidative stress, leading to ROS production, are central to ND pathology. ROS-induced damage is exacerbated by neurons' limited regenerative capacity and low antioxidant levels. This activates the MAPK signaling cascade, with ASK1, a MAP3K, promoting apoptosis via the JNK and p38 pathways under stress conditions. In our study, we targeted ASK1 to disrupt its signaling pathway by identifying a suitable inhibitor. We screened a library of 3,647 FDA-approved compounds and natural compounds derived from plants known for their anticancer and anti inflammatory properties. These plant-derived compounds were sourced from literature and databases such as the IMPPAT library. Drug discovery was performed using the AutoDock tool in PyRx, and inhibitors with the highest binding affinities and favorable biological properties were selected. ADMET analysis was conducted to ensure the selected inhibitors had acceptable pharmacokinetic and toxicological profiles. The software utilized in this study is publicly accessible, facilitating further laboratory validation of these inhibitors in model organisms. In drug discovery analysis we found the top three compounds in bot both libraries representing excellent binding affinity with the therapeutic protein. These ligands are further analyzed for their physiochemical, pharmacokinetic, and carcinogenic properties which also show remarkable results. All the analyses show good results of leading compounds for FDA drugs and phytochemicals. Phytochemicals (IMPHY003277, IMPHY001869, IMPHY010687) vi and FDA-approved drugs (amitriptylinoxide, florantyrone, ponatinib) demonstrated strong ASK1 binding, favorable pharmacokinetics, minimal toxicity, and non carcinogenic properties, making them promising candidates for neurodegenerative disease treatment. This study highlights the importance of comprehensive evaluation in drug development targeting ASK1.