BACE1 Inhibition by Genistein: Biological Evaluation, Kinetic Analysis, and Molecular Docking Simulation

Abstract

β-site amyloid precursor protein cleaving enzyme 1 (BACE1) plays a role in generating amyloid β (Aβ), thus playing a major part early in the pathogenesis of Alzheimer's disease (AD). BACE1 has emerged as a crucial therapeutic target for decreasing the Aβ concentration in the AD brain. To explore natural BACE1 inhibitors, the present study concentrated on isoflavones, including genistein, formononetin, glycitein, daidzein, and puerarin. In this study, in vitro anti-AD activities were assessed using BACE1 inhibition assays, as well as enzyme kinetic predictions. Molecular docking analysis was applied to design potential BACE1 inhibitors. Among the major isoflavones, genistein exerted a notable BACE1 inhibition through reversible noncompetitive mechanism, while other compounds were less potent against BACE1. The docking study revealed that genistein had negative binding energy (-8.5 kcal/mol) and was stably positioned in the allosteric domains of BACE1 residues. It interacted with important amino acid residues in BACE1, such as ASN37, GLN73, and TRP76, through hydrogen bonding. The results suggested that genistein may be beneficial for preventing and/or treating AD. Furthermore, it may provide potential guidelines for the design of new BACE1 inhibitors.

Traditional Chinese medicine for anti-Alzheimer’s disease: berberine and evodiamine from Evodia rutaecarpa

“…BBR has also been found to inhibit the expression of cyclin D1 and p53, keeping cells in the G0/G1 phase to prevent neuronal apoptosis [113]. The antioxidant action of BBR has been demonstrated [106,109,114] and its mechanism has also been studied. Glutathione (GSH) is an important antioxidant and Glutathione peroxidase (GPx) is a free-radical scavenger.…”

Discovery of Sulforaphane as a Potent BACE1 Inhibitor Based on Kinetics and Computational Studies

“…According to our present study, sulforaphane, as a non-competitive BACE1 inhibitor, had high selectivity for BACE1 as compared to the other aspartyl and serine proteases, indicating that the compound was a safe natural inhibitor of side effects. Many natural BACE1 inhibitors showed non-competitive modes, such as green tea catechins, stilbenoids, coumarins, citrus flavonoids, and ellagitannin [ 21 , 22 , 23 , 24 ]. A previous study by Fang et al (2017) demonstrated that non-competitive BACE1 inhibitors from natural sources deserved further study because of their non-competitive inhibition modes and different structures from those active site directed inhibitors, which may support a new approach to overcoming problems faced with competitive inhibition [ 16 ].…”

Molekularne mechanizmy działania genisteiny w świetle terapii chorób genetycznych i immunologicznych

“…amyloid precursor protein) poprzez sekretazy (β-sekretazy i γ-sekretazy) [63]. Kluczowym enzymem odpowiedzialnym za ten proces jest β-sekretaza 1 (BACE1) [64]. Youn i wsp.…”

“…Silne wiązanie powstaje w miejscu allosterycznym BACE1. Hamowanie proteazy związane jest z budową strukturalną, konkretnie z obecnością grupy hydroksylowej C-5 w pierścieniu A. Wykazano, że w wyniku działania genisteiny na enzym BACE1 dochodzi do zahamowania patologicznych procesów indukowanych poprzez βA, a co za tym idzie -zahamowania apoptozy (badania przeprowadzone zarówno na liniach komórek SHSY5Y jak i na modelach zwierzęcych) [64].…”

“…Ciekawym doniesieniem jest fakt, że obniżony poziom endogennego estrogenu znacznie zwiększa częstość występowania AD [74]. Zatem stosowanie genisteiny w leczeniu AD jest tym bardziej zasadne, że izoflawon ten wykazuje strukturalne podobieństwo do estrogenu, dzięki czemu może zastąpić te braki [64].…”