Kororamides, Convolutamines, and Indole Derivatives as Possible Tau and Dual-Specificity Kinase Inhibitors for Alzheimer's Disease: A Computational Study.

Laura Llorach-Pares,Melchor Sanchez-Martinez,Alfons Nonell-Canals,Conxita Avila

doi:10.3390/md16100386

Abstract

Alzheimer’s disease (AD) is becoming one of the most disturbing health and socioeconomic problems nowadays, as it is a neurodegenerative pathology with no treatment, which is expected to grow further due to population ageing. Actual treatments for AD produce only a modest amelioration of symptoms, although there is a constant ongoing research of new therapeutic strategies oriented to improve the amelioration of the symptoms, and even to completely cure the disease. A principal feature of AD is the presence of neurofibrillary tangles (NFT) induced by the aberrant phosphorylation of the microtubule-associated protein tau in the brains of affected individuals. Glycogen synthetase kinase-3 beta (GSK3β), casein kinase 1 delta (CK1δ), dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) and dual-specificity kinase cdc2-like kinase 1 (CLK1) have been identified as the principal proteins involved in this process. Due to this, the inhibition of these kinases has been proposed as a plausible therapeutic strategy to fight AD. In this study, we tested in silico the inhibitory activity of different marine natural compounds, as well as newly-designed molecules from some of them, over the mentioned protein kinases, finding some new possible inhibitors with potential therapeutic application.

Highlights

Constituting about 2% of all human genes, protein kinases are an important family of enzymes with a critical role in signal transduction pathway by modification of substrate activity
Protein kinases have two different lobes, the N-lobe that is mainly formed by β-sheets and the C-lobe formed by a helical structure
Between both lobes can be found the catalytic adenosine triphosphate (ATP) cavity, which can be divided into five regions: glycine-rich region (GRR), hydrophobic pocket (HP), adenine region (AR), sugar pocket (SP), and the phosphate binding pocket (PBP) [46–48]

Summary

Introduction

Constituting about 2% of all human genes, protein kinases are an important family of enzymes with a critical role in signal transduction pathway by modification of substrate activity. They are responsible to control different aspects of cell functions by its phosphorylation activity, which plays a critical role in intracellular communication during development, and in the function of the nervous and immune systems [1]. Kinases are related with many diseases, such as Alzheimer’s. Alzheimer’s pathologies are associated with the presence of senile plaques (SP), mainly composed by beta-amyloid (Aβ) peptides, and neurofibrillary tangles (NFT), that are intraneuronal aggregations principally.

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