In silico evaluation of bioactive compounds as potential inhibitors targeting HIF-1α/VEGFA/BACE1 pathway against Alzheimer's disease.

OBJECTIVES: Neurodegenerative disorders such as Alzheimer's disease (AD) are characterized by progressive neuronal degeneration, predominantly caused by the accumulation of amyloid-beta (Aβ) and neuroinflammatory processes. Hypoxia, characterized by diminished oxygen levels, intensifies these mechanisms by stimulating hypoxiainducible factor 1-alpha (HIF-1α), potentially enhancing BACE1 enzyme activity and resulting in increased Aβ synthesis and render neurons especially susceptible to hypoxia, exacerbating disease progression. Existing therapies are constrained by inadequate medication distribution across the blood-brain barrier and associated adverse effects. This study aims to identify potential therapeutic agents targeting HIF-1α, VEGFA, BACE1 key molecules involved in AD by exploring neuroprotective effects of bioactive compounds like benzyl isothiocyanate (BITC), Aurantiamide Acetate (AA), and galantamine, with the goal of developing more effective, targeted treatments.

METHODS: We used in silico screening, such as molecular docking and ADMET analysis, to assess the binding affinity, pharmacokinetics, and toxicity of potential inhibitors, followed by in vitro testing.

RESULTS: Results identified several compounds with strong binding affinities and favorable ADMET profiles as potential inhibitors of HIF-1α, VEGFA, BACE1 and experimental data support that hypoxia, via HIF-1α, upregulates BACE1, increasing Aβ production and contributing to AD. Targeting these pathways may offer a multi-faceted approach to therapy, reducing neuroinflammation and amyloid pathology.

CONCLUSIONS: In silico screening of potential molecules across different pathogenic pathways in Alzheimer's disease shows promise in developing successful therapeutic methods and continued validation may result in more tailored and safer medicines that address underlying neurodegenerative pathways.