Paudel_2019_ACS.Omega_4_6283

Cholinesterase, beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), and glycogen synthase kinase-3beta (GSK-3beta) are the three main enzymes responsible for the early onset of Alzheimer's disease (AD). The main aim of the present study was to delineate and accentuate the triple-inhibitory potential of arylbenzofurans from Morus alba against these enzymes. Overall, the enzyme inhibition assays demonstrated the prominence of mulberrofuran D2 as an inhibitor of AChE, BChE, BACE1, and GSK-3beta enzymes with IC50 values of 4.61, 1.51, 0.73, and 6.36 muM, respectively. Enzyme kinetics revealed different modes of inhibition, and in silico modeling suggested that mulberrofuran D2 inhibited these enzymes with low binding energy through hydrophilic, hydrophobic, and pi-cation interactions in the active site cavities. Similarly, in Abeta-aggregation assays, mulberrofuran D2 inhibited self-induced and AChE-induced Abeta aggregation in a concentration-dependent manner that was superior to reference drugs. These results suggest that arylbenzofurans from M. alba, especially mulberrofuran D2, are triple inhibitors of cholinesterase, BACE1, and GSK-3beta and may represent a novel class of anti-AD drugs.