Protease inhibitor from Streptomyces pulveraceus strain VITSSAB as a potential therapeutic agent against BACE1 in Alzheimer's disease: A molecular docking and dynamics simulations study

Abstract

Alzheimer's disease (AD) is a leading neurodegenerative disorder causing memory decline and loss of independence. BACE1 catalyzes amyloid precursor protein (APP) cleavage, forming amyloid-beta plaques. Inhibiting BACE1 is a key strategy to prevent plaque accumulation and develop AD therapies.

This study investigates high-altitude terrestrial-pigmented actinomycetes as a potential source of therapeutic compounds targeting BACE1 protease. Streptomyces pulveraceus VITSSAB was identified as a strong inhibitor of aspartic proteases, specifically pepsin, exhibiting a protease inhibitory activity of 66.3 ± 0.938 %. Analytical techniques, including UPLC, GC-MS, and FTIR, identified N-(Trifluoroacetyl)-N,O,O′,O″-tetrakis(trimethylsilyl)norepinephrine as the key compound responsible for the observed protease inhibition. Drug-likeness properties of N-(Trifluoroacetyl)-N,O,O′,O″-tetrakis(trimethylsilyl)norepinephrine showed favorable pharmacokinetic characteristics, reinforcing its potential as a therapeutic agent. Molecular docking studies demonstrated a strong binding affinity of −7.24 kcal/mol between this compound and BACE1 protease, indicating its efficacy in targeting the enzyme. Molecular dynamics simulations further confirmed the stability of the compound-BACE1 complex. Considering its promising characteristics, N-(Trifluoroacetyl)-N,O,O′,O″-tetrakis(trimethylsilyl)norepinephrine presents itself as a strong candidate for further development as a potential therapeutic agent targeting AD, specifically as a BACE1 inhibitor.