Abdulganiyyu et al. J Biomed & App Sci FUD (2025) 4:1
Keywords: Alzheimer's Disease, Hybrid inhibitors, Receptor, Docking, Pharmacokinetic
2026-03-27 DOI: JOBASFUD_2024_3_2_021
Abstract Background: Alzheimer’s disease (AD) is a complex neurodegenerative disorder lacking effective therapeutic solutions. Hybrid molecules with multitarget potential are gaining attention as viable candidates to slow or halt AD progression. Computational-aided drug design offers a cost-effective and efficient method to identify promising drug leads with desirable pharmacological traits. This study investigates hybrid compounds as potential inhibitors of key AD-related proteins using virtual screening, molecular docking, and pharmacokinetic profiling. Methods: Twenty-five hybrid compounds were selected for virtual screening through molecular docking against critical AD-associated enzymes and receptors. Docking scores were used to assess binding affinities and interaction strengths. Top-performing candidates were analysed using LIGPLOT+ v2.2.7 for 2D interaction maps and PyMOL v2.5 for 3D structural visualization. Furthermore, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) predictions were conducted to evaluate drug-likeness and safety profiles. Results: Out of the 25 compounds screened, ten exhibited notable binding affinities. Compounds 3 (-37.41 kcal/mol), 19 (-35.68 kcal/mol), and 20 (-36.88 kcal/mol) outperformed the reference compound (-26.30 kcal/mol) in docking scores. Key residues such as ASN349, PHE168, and SER67 were identified as critical for hydrogen bonding and hydrophobic interactions, potentially influencing neurotransmitter pathways involving dopamine and norepinephrine. ADMET predictions further indicated favourable pharmacokinetic properties and minimal toxicity. Conclusion: The study identified several promising hybrid molecules with strong in-silico inhibitory activity against AD-related targets. Their favorable binding profiles and pharmacokinetics highlight their potential as anti-AD agents. These findings provide a strong foundation for future in-vitro and in-vivo investigations aimed at validating their clinical relevance in Alzheimer’s therapy.