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

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-beta 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. 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 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. 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 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.