Computational Identification of Potent Multitarget Natural Ligands for Alzheimer's Disease Therapeutics

Alzheimer's disease (AD), a complex neurodegenerative disorder, urgently necessitates a multitarget therapeutic approach. This study presents a novel in silico framework targeting a unique combination of four AD-relevant proteins-sortilin, clusterin, tau, and amyloid-beta (Aβ)-not previously explored together in multitarget docking studies. The study leveraged a comprehensive computational strategy integrating ADME (absorption, distribution, metabolism, excretion) and ProTox-3.0 analyses with AutoDock Vina molecular docking, binding, and bond interaction via SiteMap/CASTp and PLIP, respectively. Fifteen novel natural ligands and three established AD reference drugs (donepezil, memantine, and rivastigmine) were assessed against four key AD proteins: sortilin, clusterin, Aβ peptide, and tau. Pharmacokinetic and toxicity predictions revealed favorable drug-likeness for many ligands, 4-tert-amylphenol, allicin, apigenin, and resveratrol, which exhibited high gastrointestinal absorption but varied in blood-brain barrier (BBB) permeation, solubility, and drug-likeness. Ligands, such as apigenin, cyanidin, and galantamine, demonstrated favorable oral bioavailability and lead-likeness. Nevertheless, predicted toxicity profiles revealed potential hepatotoxicity concerns for ligands like 4-tert-amylphenol and berberine. Comparison with reference drugs highlighted the importance of optimizing ADME properties and minimizing toxicity. Molecular docking results consistently highlighted ginkgolide with multitarget binding to sortilin (-16.29 kcal/mol), clusterin (-13.98 kcal/mol), and tau (-10.63 kcal/mol). Critical interactions were identified, including binding to the aggregation domain of tau via HIS329. Other promising natural ligands, including ginsenosides, berberine, and apigenin, also exhibited strong multitarget interactions. Ginsenosides were a notable lead, demonstrating key molecular contacts with ILE141 on sortilin and directly targeting the Aβ core at ALA4. Apigenin also showed strong binding to the tau repeat domain at ILE328. Notably, memantine displayed significant binding to both sortilin and Aβ, forming a hydrogen bond with the amyloidogenic ILE5 residue. The study identified several potent multitarget binding capabilities compounds, offering compelling avenues for developing novel, more effective therapeutics for AD.