Saad_2026_J.Comput.Aided.Mol.Des_40_

This study investigates the inhibitory effects of 5 bioactive compounds isolated from Fernandoa adenophylla on two key enzymes involved in neurodegenerative diseases, Beta-secretase 1 (BACE-1) and monoamine oxidase-B (MAO-B). The compounds, namely lapachol (1), alpha-lapachone (2), peshawaraquinone (3), dehydro-alpha-lapachone (4), and the indanone derivative methyl 1,2-dihydroxy-2-(3-methylbut-2-enyl)-3-oxoindene-1-carboxylate (5) were tested in vitro and investigated by means of computational tools. Lapachol (1) resulted to be the most effective BACE-1 inhibitor of the set, while peshawaraquinone (3) strongly inhibited MAO-B. Enzyme kinetic analyses were carried out, and the inhibitory mechanisms were also elucidated. Molecular docking studies showed that the compounds target key residues in the active sites of the enzymes and density functional theory (DFT) investigation suggested a higher reactivity of lapachol (1) towards electron transfer. Overall, the findings support the potential role of these natural compounds as BACE-1 and MAO-B inhibitors.