Computational analysis on FR258900 as dual-target inhibitor of bace-1 and acetylcholinesterase in treatment of Alzheimer’s disease: A combined molecular docking and ADMET study

Introduction: Alzheimer's disease (AD) has a multifactorial pathogenesis. Single-target agents targeting amyloid-β accumulation or cholinergic dysfunction have limitations, necessitating novel therapeutic strategies. This study investigates the novel compound FR258900 to evaluate its dual-target inhibitory potential against BACE-1 and AChE. Methods: The inhibitory profile of FR258900 was assessed by in silico molecular docking using the prepared crystal structures of human BACE-1 (PDB ID: 5HDZ) and AChE (PDB ID: 6TT0), from which non-essential atoms had been removed. Reference inhibitors were included for comparison. A comprehensive ADMET profile was generated using computational tools to evaluate pharmacokinetic properties, safety, ADME characteristics, and toxicity risks. Results: The docking studies demonstrated favorable binding affinities of FR258900 for both BACE-1 and AChE. ADMET analysis forecasted low gastrointestinal absorption and poor blood-brain barrier penetration—probably attributable to P-glycoprotein (P-gp) efflux. The compound exhibited a satisfactory cytochrome P450 interaction profile and no predicted toxicity liabilities. Conclusion: Although FR258900 exhibits unfavorable pharmacokinetic properties hindering central nervous system penetration, its low toxicity and dual-target inhibition of BACE-1 and AChE position it as a promising lead compound. Further optimization is warranted to advance FR258900 as a multitarget-directed ligand for the treatment of AD.