FOCUSED INSIGHTS INTO ALZHEIMER’S TREATMENT STRATEGIES: PHARMACOPHORE MODELLING, DFT STUDIES, MD SIMULATIONS AND SH-SY5Y NEUROPROTECTION OF NARINGIN

Objective: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder involving oxidative stress, protein aggregation, and neurotransmitter imbalance. This study aimed to evaluate the neuroprotective potential of Drynaria quercifolia (DQ) phytoconstituents, particularly DQ5 (naringin), using in silico, in vitro, and pharmacological analyses for multitargeted AD therapy.

Methods: Phytocompounds from DQ were analysed through molecular docking to assess binding affinities with AD-related targets, including acetylcholinesterase (AChE), monoamine oxidase-B (MAO-B), and peroxiredoxin-5 (Prdx-5). DQ5 (naringin) was further evaluated using molecular dynamics (MD) simulations and pharmacophore modelling. Density Functional Theory (DFT) was employed to assess molecular stability and reactivity. In vitro assays measured AChE, MAO-B, tyrosinase inhibition, and hydrogen peroxide scavenging. Neuroprotective effects were evaluated using MTT assay on SH-SY5Y neuroblastoma cells.

Results: Molecular docking showed strong binding of DQ5 to AChE (-14.182 kcal/mol) and MAO-B (-13.393 kcal/mol). MD simulations confirmed complex stability. DQ5 (naringin) exhibits high stability in its gas-phase optimised structure, and its small HOMO-LUMO gap indicates it may be quite reactive, which could contribute to its biological activity. DQ5 inhibited AChE (IC₅₀ = 8.05±1.02 µg/ml) and 90% SH-SY5Y cell viability. Pharmacokinetic predictions supported favourable drug-likeness and safety profiles.

Conclusion: DQ5 (naringin), a key metabolite from DQ, exhibits significant multitarget activity against AD-related enzymes and oxidative stress. The compound's pharmacological properties and neuroprotective effects highlight its promise as a natural therapeutic candidate for addressing multiple pathways involved in AD pathogenesis.