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

  • J Alzheimers Dis. 2025 Feb;103(4):1191-1215. doi: 10.1177/13872877241313049.
Isreal Ayobami Onifade  1 ,  Haruna Isiyaku Umar  2  3 ,  Abdullahi Tunde Aborode  4 ,  Aeshah A Awaji  5 ,  Ifeoluwapo Deborah Jegede  6 ,  Bunmi Helen Adeleye  7 ,  Dorcas Oladayo Fatoba  8 ,  Ridwan Opeyemi Bello  9 ,  Sodiq Fakorede  10 ,  Nike Idowu  11
Affiliations
  • 1. Department of Biological Sciences, University at Albany - State University of New York, Albany, NY, USA.
  • 2. Department of Biochemistry, Federal University of Technology, Akure, Nigeria.
  • 3. Computer-Aided Therapeutic Discovery and Design Platform, Federal University of Technology, Akure, Nigeria.
  • 4. Department of Research and Development, Healthy Africans Platform, Ibadan, Nigeria.
  • 5. Department of Biology, Faculty of Science, University College of Taymaa, University of Tabuk, Tabuk, Saudi Arabia.
  • 6. Department of Biotechnology, Syracuse University, New York, NY, USA.
  • 7. Department of Public Health, University of Huddersfield, Huddersfield, UK.
  • 8. The University of Tennessee Health Science Center, Memphis, TN, USA.
  • 9. Faculty of Medicine, University of Queensland, Brisbane, Australia.
  • 10. Department of Physical Therapy, Rehabilitation Science, and Athletic Training, University of Kansas Medical Center, Kansas City, KS, USA.
  • 11. Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE, USA.
PMID: 39956948 DOI: 10.1177/13872877241313049
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.

Keywords
Alzheimer's disease; alkaloids; virtual docking; β- and γ-secretase inhibitors.
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