Abstract

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.

Highlights

  • Alzheimer’s disease (AD) is a rapidly growing form of dementia affecting millions of people globally with devastating consequences to the patients and their families

  • Amyloid-β and Tau pathways leading to amyloid plaques and neurofibrillary tangles (NFTs), respectively, are the central point of research for the development of AD therapies

  • Alzheimer’s is a neurodegenerative disease characterized by progressive neuronal death/loss and synapses loss in human brain

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Summary

Introduction

Alzheimer’s disease (AD) is a rapidly growing form of dementia affecting millions of people globally with devastating consequences to the patients and their families. There is a high failure rate of drugs in clinical trials indicating the need for more intensive efforts regarding the development of new small molecule inhibitors [12]. Such compounds are excellent research tools in the hands of researchers working on developing novel therapeutic strategies for AD. Examples for the application of CADD including computational structure-based design and ligand-based design approaches for the development of β-secretase, γ-secretase, anti-amyloid aggregation and anti-Tau phosphorylation, acetylation, and aggregation small molecule inhibitors and modulators are summarized as well

The Amyloid-β Pathway and its Druggable Targets
CADD for the Development of BACE1 Inhibitors
CADD for the Development of γ-Secretase Inhibitors
CADD for the Development of Anti-Aβ Aggregation Inhibitors
Therapeutic Strategies Targeting Tau in Tauopathies
Function and Structure of Tau
CADD for the Development of Anti-Tau Inhibitors
Future Perspectives
Findings
Conclusions
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