Computer-aided drug design of β-secretase, γ- secretase and anti-tau inhibitors for the discovery of novel alzheimer’s therapeutics

Varnavas D. Mouchlis, Georgia Melagraki, Lefteris C. Zacharia, Antreas Afantitis

Research output: Contribution to journalReview articlepeer-review


Aging-associated neurodegenerative diseases, which are characterized by progressive neuronal death and synapses loss in human brain, are rapidly growing affecting millions of people globally. Alzheimer’s is the most common neurodegenerative disease and it can be caused by genetic and environmental risk factors. This review describes the amyloid-β and Tau hypotheses leading to amyloid plaques and neurofibrillary tangles, respectively which are the predominant pathways for the development of anti-Alzheimer’s small molecule inhibitors. The function and structure of the druggable targets of these two pathways including β-secretase, γ-secretase, and Tau are discussed in this review article. Computer-Aided Drug Design including computational structure-based design and ligand-based design have been employed successfully to develop inhibitors for biomolecular targets involved in Alzheimer’s. The application of computational molecular modeling for the discovery of small molecule inhibitors and modulators for β-secretase and γ-secretase is summarized. Examples of computational approaches employed for the development of anti-amyloid aggregation and anti-Tau phosphorylation, proteolysis and aggregation inhibitors are also reported.

Original languageEnglish
Article number703
JournalInternational Journal of Molecular Sciences
Issue number3
Publication statusPublished - 1 Feb 2020


  • Alzheimer’s disease
  • Cheminformatics
  • Computational ligand-based design
  • Computational structure-based design
  • Computer-aided drug design
  • Molecular docking
  • Molecular dynamics
  • QSAR
  • Tau
  • β-secretase
  • γ-secretase


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