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

Gyutae Lim,Kumju Youn,Shengmin Sang,Jeong-Hyun Yoon,Chi-Tang Ho,Mira Jun,Jinhyuk Lee,Nayoung Lee

doi:10.3390/nu12103026

Abstract

BACE1 is the rate-limiting enzyme involved in the production and deposition of β-amyloid (Aβ). Since neurotoxic Aβ plays a critical role in Alzheimer’s disease (AD) pathogenesis, BACE1 has emerged as a key target for preventing AD. In the present study, the potential of sulforaphane, an isothiocyanate found in cruciferous vegetables, as a BACE1 inhibitor has been investigated. Sulforaphane exhibited six times more potent activity against BACE1 compared to well-known positive controls including resveratrol and quercetin. Sulforaphane presented selective and non-competitive BACE1 inhibitory activity with low off-target inhibition of BACE2 and other aspartic and serine proteases. In addition, sulforaphane presented negative binding energy, suggesting that the compound had a high affinity for BACE1. It interacted with locations other than the active binding sites of BACE1 through van der Waals forces. Overall, sulforaphane appeared to be a promising candidate with potent and selective BACE1 inhibitory properties that play an important role in AD prevention.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by cognitive declines and memory impairments
According to the Dixon and Lineweaver–Burk plots, sulforaphane suppressed BACE1 in non-competitive mode with a Ki value of 3.1 μM, which demonstrated that the compound interacted at sites other than the catalytic sites of BACE1 (Figure 1)
Published natural BACE1 inhibitors with various structural types, such as catechins, flavonoids, stilbenes, tannins, coumarins, chromones, and others, exhibit inhibitory activity, with IC50 values ranging from >200 μM to 1.6 μM [16], which suggests that sulforaphane demonstrates to be a potent BACE1 suppressor with low micromolar potency

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by cognitive declines and memory impairments. The primary factor initiating the pathological event in AD, is derived from the successive cleavage of amyloid precursor protein (APP) by β-and γ-secretase in the brain [2]. Β-site amyloid precursor protein cleaving enzyme 1 (BACE1), the main form of β-secretase, is a membrane-bound aspartyl protease expressed mainly in the central nervous system (CNS). It has been demonstrated that BACE1 gene deletion leads to the inhibition of Aβ accumulation and improvement of cognitive impairments in APP transgenic mice [4,5]. Molecular docking simulation was used to analyze whether the compound can reach the target enzyme to produce the biological effect safely and interact with the targeted sites

Reagent

In Silico Docking Simulation

Results and Discussion

BACE1 Specificity of Sulforaphane

Molecular Docking Simulation of Sulforaphane

Conclusions