Targeting JNK3: An In-silico Approach to Uncover Potential Therapeutics for Alzheimer's Disease

JNK3 is a specific isoform of c-Jun N-terminal kinase, mainly found in the brain, and is highly sensitive to stress-associated signals in the central nervous system. It has been reported that JNK3 plays a crucial role in neurite formation and cognition. During pathological states such as Alzheimer's disease, cerebral ischemia, Traumatic brain injury (TBI), Parkinson's disease, and epilepsy, it is found to be in a hyperactivated form. Hyperphosphorylation of amyloid precursor protein (APP) and tau leads to toxic Aβ42 and neurofibrillary tangles. Excess Aβ activates JNK3 signaling, causing neuronal loss. JNK3 also contributes to mitochondrial dysfunction, Oxidative stress, neuroinflammation, and apoptosis, driving AD progression.

This study aims to identify possible therapeutics based on their physicochemical, ADMET, toxicity, and drug-likeness properties. Moreover, we utilized Molecular docking and Molecular dynamics (MD) simulation to reveal possible inhibitors against JNK3.

Based on the highest binding affinity against JNK3, the best compounds, Myricetin and Kaempferol, were subjected to an MD simulation study. RMSD analysis indicated that the JNK3- Kampferol complex showed more stability; at the same time, myricetin formed more hydrogen bonds with JNK3. Moreover, both compounds exhibited favorable ADMET properties.

This study identified Kaempferol and myricetin as potential inhibitors that target JNK3 through molecular docking and MD simulation studies. Both compounds demonstrated favorable ADMET profiles, supporting their promise as safe, orally available drug candidates.

Therefore, Kaempferol and myricetin emerge as promising candidates for further investigations in both in vitro and in vivo studies to treat Alzheimer's disease and other neurodegenerative disorders.