Inhibition of MARK4 by serotonin as an attractive therapeutic approach to combat Alzheimer's disease and neuroinflammation

Shamsi, Anas; DasGupta, Debarati; Alhumaydhi, Fahad A.; Khan, Mohd Shahnawaz; Alsagaby, Suliman A.; Abdulmonem, Waleed Al; Hassan, Md. Imtaiyaz; Yadav, Dharmendra Kumar

doi:10.1039/d2md00053a

Cited by 13 publications

(19 citation statements)

References 44 publications

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“…This obtained binding constant reveals the significant strength of the interaction of Mtf with MARK4. Earlier studies have reported other MARK4 inhibitors [ 22 , 23 ], which were also having similar magnitudes of the binding constant suggesting the significance of this interaction and also highlighting the potency of Mtf to act as strong MARK4 inhibitor that will be further evaluated making use of the ATPase assay.…”

Section: Resultsmentioning

confidence: 71%

Inhibition of Microtubule Affinity Regulating Kinase 4 by Metformin: Exploring the Neuroprotective Potential of Antidiabetic Drug through Spectroscopic and Computational Approaches

et al. 2022

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Microtubule affinity regulating kinase 4 (MARK4) regulates the mechanism of microtubules by its ability to phosphorylate the microtubule-associated proteins (MAP’s). MARK4 is known for its major role in tau phosphorylation via phosphorylating Ser262 residue in the KXGS motif, which results in the detachment of tau from microtubule. In lieu of this vital role in tau pathology, a hallmark of Alzheimer’s disease (AD), MARK4 is a druggable target to treat AD and other neurodegenerative disorders (NDs). There is growing evidence that NDs and diabetes are connected with many pieces of literature demonstrating a high risk of developing AD in diabetic patients. Metformin (Mtf) has been a drug in use against type 2 diabetes mellitus (T2DM) for a long time; however, recent studies have established its therapeutic effect in neurodegenerative diseases (NDs), namely AD, Parkinson’s disease (PD) and amnestic mild cognitive impairment. In this study, we have explored the MARK4 inhibitory potential of Mtf, employing in silico and in vitro approaches. Molecular docking demonstrated that Mtf binds to MARK4 with a significant affinity of −6.9 kcal/mol forming interactions with binding pocket’s critical residues. Additionally, molecular dynamics (MD) simulation provided an atomistic insight into the binding of Mtf with MARK4. ATPase assay of MARK4 in the presence of Mtf shows that it inhibits MARK4 with an IC50 = 7.05 µM. The results of the fluorescence binding assay demonstrated significant binding of MARK4 with a binding constant of 0.6 × 106 M−1. The present study provides an additional axis towards the utilization of Mtf as MARK4 inhibitor targeting diabetes with NDs.

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Section: Resultsmentioning

confidence: 71%

Inhibition of Microtubule Affinity Regulating Kinase 4 by Metformin: Exploring the Neuroprotective Potential of Antidiabetic Drug through Spectroscopic and Computational Approaches

et al. 2022

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“…Consequently, an overexpression of MARK4 is associated with numerous neurodegenerative disorders and neuropathy [ 57 , 58 ]. Thus, inhibiting MARK4 can be considered essential to cure some neurodegenerative diseases, including AD [ 59 , 60 ].…”

Section: 5-ht 6 R/mark4 As Dual Target Approach In...mentioning

confidence: 99%

“…Furthermore, recent lines of evidence, based on the fluorescence binding study, isothermal calorimetry, molecular docking and MD simulation studies for estimating the binding affinity and inhibiting potential of serotonin with MARK4, have demonstrated serotonin as an inhibitor of this important kinase. Hence, targeting MARK4 by serotonin opens a “new gate” in managing the clinical manifestations of neurodegenerative diseases such as AD and dementia [ 60 ].…”

Section: 5-ht 6 R/mark4 As Dual Target Approach In...mentioning

confidence: 99%

“…In order to compare the activity expressed in various ways (IC50, K d or %inhibition at a given concentration), a formal inhibition activity descriptor (FA) was used (Figure 6, Table S1 in Supplementary Materials). the weak 3-N-aryl substituted-2-heteroarylchromoneinhibitor 14 [54] in comparison to the moderate 3-benzoylcoumarinMARK4 inhibitor; (b) the moderate inhibitors from various heterocyclic families 15 [55], 16 [56], 17 [57], 18 [58], 19 [59], 20 [60], 21 [61]; (c) MARK4 inhibitory properties of rivastigmine and donepezil [50]. To compare the activity expressed in various ways (IC50, Kd or %inhibition at a given concentration), the formal inhibition activity descriptor (FA) was used, i.e.,: FA = pIC50 (IC50); FA = pKd (Kd), FA = p(test concentration/0.02 × %inhibition).…”

Section: -Ht 6 R/mark4 As Dual Target Approach In Search For Therapeu...mentioning

confidence: 99%

“…The active MARK4 inhibitors, described with submicromolar to have a low-nanomolar range of action, contain the indispensable central core of the pyrimidine, which appears to be a required pharmacophore feature in interactions with this kinase, while a variety of the remaining substitutions enhances the inhibitory power [69][70][71][72][73][74] [54] in comparison to the moderate 3-benzoylcoumarinMARK4 inhibitor; (b) the moderate inhibitors from various heterocyclic families 15 [55], 16 [56], 17 [57], 18 [58], 19 [59], 20 [60], 21 [61]; (c) MARK4 inhibitory properties of rivastigmine and donepezil [50]. To compare the activity expressed in various ways (IC50, Kd or %inhibition at a given concentration), the formal inhibition activity descriptor (FA) was used, i.e.,: FA = pIC50 (IC50); FA = pKd (Kd), FA = p(test concentration/0.02 × %inhibition).…”

Section: -Ht 6 R/mark4 As Dual Target Approach In Search For Therapeu...mentioning

confidence: 99%

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Multitargeting the Action of 5-HT6 Serotonin Receptor Ligands by Additional Modulation of Kinases in the Search for a New Therapy for Alzheimer’s Disease: Can It Work from a Molecular Point of View?

Czarnota-Łydka

Kucwaj-Brysz

Pyka

et al. 2022

IJMS

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In view of the unsatisfactory treatment of cognitive disorders, in particular Alzheimer’s disease (AD), the aim of this review was to perform a computer-aided analysis of the state of the art that will help in the search for innovative polypharmacology-based therapeutic approaches to fight against AD. Apart from 20-year unrenewed cholinesterase- or NMDA-based AD therapy, the hope of effectively treating Alzheimer’s disease has been placed on serotonin 5-HT6 receptor (5-HT6R), due to its proven, both for agonists and antagonists, beneficial procognitive effects in animal models; however, research into this treatment has so far not been successfully translated to human patients. Recent lines of evidence strongly emphasize the role of kinases, in particular microtubule affinity-regulating kinase 4 (MARK4), Rho-associated coiled-coil-containing protein kinase I/II (ROCKI/II) and cyclin-dependent kinase 5 (CDK5) in the etiology of AD, pointing to the therapeutic potential of their inhibitors not only against the symptoms, but also the causes of this disease. Thus, finding a drug that acts simultaneously on both 5-HT6R and one of those kinases will provide a potential breakthrough in AD treatment. The pharmacophore- and docking-based comprehensive literature analysis performed herein serves to answer the question of whether the design of these kind of dual agents is possible, and the conclusions turned out to be highly promising.

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Synthesis of 3‐hydroxy‐2‐naphthohydrazide‐based hydrazones and their implications in diabetic management via in vitro and in silico approaches

Tasleem,

Ullah,

Halim

et al. 2023

Archiv der Pharmazie

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Diabetes mellitus (DM) has prevailed as a chronic health condition and has become a serious global health issue due to its numerous consequences and high prevalence. We have synthesized a series of hydrazone derivatives and tested their antidiabetic potential by inhibiting the essential carbohydrate catabolic enzyme, “α‐glucosidase.” Several approaches including fourier transform infrared, 1H NMR, and 13C NMR were utilized to confirm the structures of all the synthesized derivatives. In vitro analysis of compounds 3a–3p displayed more effective inhibitory activities against α‐glucosidase with IC50 in a range of 2.80–29.66 µM as compared with the commercially available inhibitor, acarbose (IC50 = 873.34 ± 1.67 M). Compound 3h showed the highest inhibitory potential with an IC50 value of 2.80 ± 0.03 µM, followed by 3i (IC50 = 4.13 ± 0.06 µM), 3f (IC50 = 5.18 ± 0.10 µM), 3c (IC50 = 5.42 ± 0.11 µM), 3g (IC50 = 6.17 ± 0.15 µM), 3d (IC50 = 6.76 ± 0.20 µM), 3a (IC50 = 9.59 ± 0.14 µM), and 3n (IC50 = 10.01 ± 0.42 µM). Kinetics analysis of the most potent compound 3h revealed a concentration‐dependent form of inhibition by 3h with Ki value = 4.76 ± 0.0068 µM. Additionally, an in silico docking approach was applied to predict the binding patterns of all the compounds, which indicates that the hydrazide and the naphthalene‐ol groups play a vital role in the binding of the compounds with the essential residues (i.e., Glu277 and Gln279) of the α‐glucosidase enzyme.

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Inhibition of MARK4 by serotonin as an attractive therapeutic approach to combat Alzheimer's disease and neuroinflammation

Abstract: The mitogen-activated protein kinases (MAPKs) govern various cellular programs and crucial intermediate pathways in signaling. Microtubule affinity-regulating kinase 4 (MARK4) is a part of the kinase family recognized for actively...

Cited by 13 publications

References 44 publications

Inhibition of Microtubule Affinity Regulating Kinase 4 by Metformin: Exploring the Neuroprotective Potential of Antidiabetic Drug through Spectroscopic and Computational Approaches

Inhibition of Microtubule Affinity Regulating Kinase 4 by Metformin: Exploring the Neuroprotective Potential of Antidiabetic Drug through Spectroscopic and Computational Approaches

Multitargeting the Action of 5-HT6 Serotonin Receptor Ligands by Additional Modulation of Kinases in the Search for a New Therapy for Alzheimer’s Disease: Can It Work from a Molecular Point of View?

Synthesis of 3‐hydroxy‐2‐naphthohydrazide‐based hydrazones and their implications in diabetic management via in vitro and in silico approaches

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