Computer-Aided Drug Design Applied to Marine Drug Discovery: Meridianins as Alzheimer's Disease Therapeutic Agents.

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

doi:10.3390/md15120366

Laura Llorach-Pares, Laura Llorach-Pares + Show 4 more

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https://doi.org/10.3390/md15120366

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Abstract

Computer-aided drug discovery/design (CADD) techniques allow the identification of natural products that are capable of modulating protein functions in pathogenesis-related pathways, constituting one of the most promising lines followed in drug discovery. In this paper, we computationally evaluated and reported the inhibitory activity found in meridianins A–G, a group of marine indole alkaloids isolated from the marine tunicate Aplidium, against various protein kinases involved in Alzheimer’s disease (AD), a neurodegenerative pathology characterized by the presence of neurofibrillary tangles (NFT). Balance splitting between tau kinase and phosphate activities caused tau hyperphosphorylation and, thereby, its aggregation and NTF formation. Inhibition of specific kinases involved in its phosphorylation pathway could be one of the key strategies to reverse tau hyperphosphorylation and would represent an approach to develop drugs to palliate AD symptoms. Meridianins bind to the adenosine triphosphate (ATP) binding site of certain protein kinases, acting as ATP competitive inhibitors. These compounds show very promising scaffolds to design new drugs against AD, which could act over tau protein kinases Glycogen synthetase kinase-3 Beta (GSK3β) and Casein kinase 1 delta (CK1δ, CK1D or KC1D), and dual specificity kinases as dual specificity tyrosine phosphorylation regulated kinase 1 (DYRK1A) and cdc2-like kinases (CLK1). This work is aimed to highlight the role of CADD techniques in marine drug discovery and to provide precise information regarding the binding mode and strength of meridianins against several protein kinases that could help in the future development of anti-AD drugs.

Highlights

IntroductionDrug discovery is the process of identifying new molecules with a certain therapeutic activity
Drug discovery is the process of identifying new molecules with a certain therapeutic activity.This process is very expensive in terms of money and time
This work is aimed to highlight the role of Computer-aided drug discovery/design (CADD) techniques in marine drug discovery and to provide precise information regarding the binding mode and strength of meridianins against several protein kinases that could help in the future development of anti-Alzheimer’s disease (AD) drugs

Summary

Introduction

Drug discovery is the process of identifying new molecules with a certain therapeutic activity. This process is very expensive in terms of money and time. Translating basic research to the market (going through drug discovery, preclinical and clinical studies) takes tens of years and costs billions of dollars. The average cost to develop a new molecular entity is estimated to be $1.8 billion and requires about 13.5 years [1]. The usage of computational techniques at various stages of the drug discovery process could reduce that cost [2].

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