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

Alzheimer's 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 β-amyloid 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. 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. From our results, 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 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. Keywords: β- and γ-Secretase inhibitors, Alzheimer's disease, alkaloids, Virtual docking