Unveiling the Polypharmacological Potency of FDA-Approved Rebamipide for Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterised by the accumulation of neurotoxic substances in the brain, ultimately leading to progressive cognitive decline. The complex aetiology and involvement of multiple molecular targets in AD pathogenesis have made discovering effective therapeutic agents particularly challenging. Targeting multiple proteins simultaneously with a single therapeutic agent may offer a promising strategy to address the disease's multifaceted nature. This study employed advanced computational methodologies to perform multitargeted molecular docking of FDA-approved drugs against four key AD-associated proteins implicated in disease progression. Among the screened compounds, Rebamipide-a drug conventionally used for treating gastrointestinal disorders-demonstrated notable binding affinities across all targets. Pharmacokinetic predictions, interaction fingerprinting, WaterMap analysis, density functional theory (DFT) calculations, and 100 ns MD simulations were performed for each protein-ligand complex to evaluate its multitarget potential. Rebamipide bound effectively to the NR1 ligand-binding core, suggesting modulation of glutamatergic signalling while reducing β-secretase production and regulating neurotransmitter homeostasis through inhibiting monoamine oxidase-A. Furthermore, Rebamipide enhanced cholinergic neurotransmission by inhibiting human acetylcholinesterase, potentially improving cognitive function. Pharmacokinetic analyses confirmed favourable drug-like properties. Molecular interaction fingerprints revealed consistent hydrogen bonding, hydrophobic contacts, and π-π stacking interactions. WaterMap analysis indicated thermodynamically favourable water displacement upon binding, enhancing ligand affinity. DFT analysis of Rebamipide showed a 4.24 eV HOMO-LUMO gap, with ESP values ranging from -6.63 × 10 to +6.63 × 10 A.U., indicating reactive sites. TDDFT predicted strong UV absorption at 314 nm with a peak intensity of ~6500 L mol cm. MD simulations over 100 ns demonstrated minimal structural deviations and stable ligand-protein complexes, reinforcing its multitarget efficacy. The comprehensive in silico investigation highlights Rebamipide as a promising multitargeted therapeutic candidate for Alzheimer's disease. Its ability to modulate multiple pathogenic pathways simultaneously underscores its potential utility; however, these computational findings warrant further experimental validation to confirm its efficacy and therapeutic relevance in AD.