Targeting p38 MAPK: Molecular Docking and Therapeutic Insights for Alzheimer’s Disease Management

Background: Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is closely linked to the p38 mitogen-activated protein kinase (MAPK) pathway, which regulates neuroinflammation, oxidative stress, apoptosis, and other key pathological processes. Developing selective inhibitors targeting p38 MAPK could offer novel therapeutic interventions for AD. Methods: Nine molecules, selected for their therapeutic potential based on literature, were docked against p38 MAPK (5MTX) using molecular docking. Binding affinities, hydrogen bonding, and hydrophobic interactions were analyzed to assess the strength and stability of ligand-receptor interactions. Residues contributing to selectivity and therapeutic potential were identified, and results were contextualized with in vitro and in vivo studies. Results: NJK14047 exhibited the highest binding affinity (-10.2 kcal/mol) due to hydrogen bonds with Asn115, Gly110, Met109, Asp168, and Glu71, contributing to enhanced stability and selectivity. Ginsenoside Rg1 (-7.9 kcal/mol) and Apigenin (-8.7 kcal/mol) demonstrated significant interactions with key residues, including Thr106 and Leu104, with Ginsenoside Rg1 supporting mitophagy and memory improvement in AD models. Skepinone-L showed high inhibitory activity with hydrophobic residues but lacked hydrogen bonding. In vivo studies supported the neuroprotective and anti-inflammatory effects of several candidates, with NJK14047 reducing microglial activation and promoting neuroprotection. Conclusion: The study underscores the therapeutic potential of p38 MAPK inhibitors in AD management. NJK14047, with its strong binding affinity and selectivity, emerges as a lead candidate for further exploration. These findings highlight the need for clinical trials to validate the efficacy of p38 MAPK inhibitors as a comprehensive approach to treating AD.