In silico study of selected alkaloids as dual inhibitors of β- and γ-secretases for Alzheimer's disease

Abstract

Background

Alzheimer's disease (AD) has become common as the number of aged people increases making it as a socioeconomic problem lately. To date, no success is recorded for disease-modifying therapies for AD but only drugs for symptomatic relief exist. Research has been centered on the role of amyloid-β on the pathogenesis of AD, which has led to the development of drugs that target Aβ (β- and γ-secretase inhibitors) to reduce the amount of Aβ formed. However, the existing β and γ-secretase inhibitors were associated with harmful side effects, low efficacy, and inability to cross the blood-brain barrier.

Objective

This study therefore used in silico approach to predict the inhibitory properties of alkaloids as potential drug targets against AD.

Methods

Thus, in this current study, 54 alkaloids from the PhytoHub server (phytohub.eu), and two approved drugs were docked against β-secretases. Additionally, galantamine and 5 alkaloids with the utmost binding potential with β-secretase were subjected to pharmacokinetics evaluation and docked against γ-secretase.

Results

From the result, 5 compounds displayed for both docking periods, with demissidine, solasodine, tomatidine, and solanidine having better BE than the control drugs. Based on the pharmacokinetics evaluation, 4 compounds possessed good pharmacokinetic evaluation and biological activities than galantamine.

Conclusions

This study suggests that demissidine, solasodine, tomatidine, and solanidine are promising dual inhibitors against β- and γ-secretase proteins in silico. However, there is an urgent need to carry out in vitro and in vivo experiments on these new leads to validate the findings of this study.