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

Abstract

Alzheimers disease (AD) has become ubiquitous as the number of elderly individuals increases and has been conceived 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 {beta}-amyloid on the pathogenesis of AD, which has led to the development of drugs that target A{beta} ({beta} and {gamma}-Secretase inhibitors) to reduce the amount of A{beta} formed. However, the existing {beta} and {gamma}-Secretase inhibitors were associated with harmful side effects, low efficacy, and inability to cross the blood-brain barrier. Thus, in this current study, 54 alkaloids from the PhytoHub server (phytohub.eu), and two approved drugs were docked against {beta}-Secretases. Additionally, galantamine and 5 alkaloids with the utmost binding potential with {beta}-secretase were subjected to pharmacokinetics evaluation and docked against {gamma}-secretase. . From our 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. This study suggests that demissidine, solasodine, tomatidine, and solanidine are promising dual inhibitors against {beta} and {gamma}-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.