In silico Identification of BACE-1 Inhibitory Potential of Indicol from Mangifera indica for Targeting Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques, primarily formed through the enzymatic action of beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1). There are many synthetic compounds demonstrating severe side effects that are used to inhibit BACE-1 in AD patients. The exploration for traditional phytocompounds to inhibit BACE-1 remains elusive. This study aims to identify and evaluate the potential BACE-1 inhibitory activity of phytocompounds found in Mangifera indica. We employed two different molecular docking methods, along with molecular dynamics simulations and ADME/Tox analysis, to elucidate two potential phytocompounds that exhibit BACE-1 inhibiting mechanisms. The first phytocompound Indicol showed effective blood-brain barrier (BBB) permeability, binding affinity of -6.65 kcal/mol, and significant hydrogen bond formation with crucial BACE-1 residues (Gln73, Lys107, Gly230, Thr232). The second phytocompound Cyclocolorenone screened through MM/GBSA analysis demonstrated comparatively weaker interactions and lower binding affinity with BACE-1. The Molecular dynamics simulations also indicated that Indicol maintained stable interactions over a 100 ns simulation, whereas Cyclocolorenone showed less consistent binding. The findings suggest that Indicol from Mangifera indica is a promising candidate for BACE-1 inhibition, demonstrating strong binding affinity and stability in silico. The results warrant further experimental validation to explore the therapeutic potential of Indicol in the treatment of Alzheimer’s disease.