Meridianin derivatives as potent Dyrk1A inhibitors and neuroprotective agents

Yadav, Rammohan R.; Sharma, Sumit; Joshi, Prashant; Wani, Abubakar; Vishwakarma, Ram A.; Kumar, Ajay; Bharate, Sandip B.

doi:10.1016/j.bmcl.2015.05.034

Cited by 37 publications

(25 citation statements)

References 25 publications

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“…The four protein kinases studied here were previously described by other authors as meridianin targets [ 25 , 32 , 50 , 51 ]. This constitutes an excellent validation of our computational, blind, approach to identify the biological profile of meridianins.…”

Section: Discussionmentioning

confidence: 99%

“…This constitutes an excellent validation of our computational, blind, approach to identify the biological profile of meridianins. However, although in the literature the possible anti-AD activity of meridianins was reported and several compounds have been designed from them [ 25 , 32 , 50 , 51 ], several aspects have not been taken into account and analysed, from a target-based (structural) perspective, as we have done here.…”

Section: Discussionmentioning

confidence: 99%

“…It was carried out through a bibliographical search plus a database analysis. The bibliographical search was conducted using several studies in which inhibitors against the selected kinases were identified describing each compound binding mode [ 25 , 31 , 32 , 50 , 51 , 52 , 64 , 81 , 82 ]. The database search was done using an in-house, recently constructed database.…”

Section: Methodsmentioning

confidence: 99%

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

Llorach-Parés

Nonell-Canals²,

Sánchez-Martínez³

et al. 2017

Marine Drugs

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

Llorach-Parés

Nonell-Canals²,

Sánchez-Martínez³

et al. 2017

Marine Drugs

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“…AD is not an exception, and several drug candidates have been developed from natural sources against the different therapeutic targets identified to date [ 21 , 22 , 23 ]. In fact, few reasonable selective and potent GSK3β, CK1δ, DYRK1A, and CLK1 inhibitors have been described so far, most of them being marine natural products or derived molecules from them [ 5 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, it has been shown that meridianins, indole alkaloids from the marine tunicate Aplidium from the Southern Ocean, could act as inhibitors of these four kinases, with possible inhibitors being derived from them [ 24 , 29 , 34 , 37 ]. In addition to that, kororamide A–B, two brominated alkaloids from the bryozoan Amathia tortuosa from Australia, showed a phenotypic signature on Parkinson's disease [ 38 ].…”

Section: Introductionmentioning

confidence: 99%

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

Llorach-Parés

Nonell-Canals²,

Ávila

et al. 2018

Marine Drugs

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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.

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A Dual Inhibitor of DYRK1A and GSK3β for β‐Cell Proliferation: Aminopyrazine Derivative GNF4877

et al. 2020

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Loss of β‐cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β‐cell mass are less developed. Promoting β‐cell proliferation with low‐molecular‐weight inhibitors of dual‐specificity tyrosine‐regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β‐cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β) was previously reported to induce primary human β‐cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high‐throughput screening campaign measuring β‐cell proliferation.

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Meridianin derivatives as potent Dyrk1A inhibitors and neuroprotective agents

Cited by 37 publications

References 25 publications

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

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

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

A Dual Inhibitor of DYRK1A and GSK3β for β‐Cell Proliferation: Aminopyrazine Derivative GNF4877

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