Targeting inhibition of microtubule affinity regulating kinase 4 by Harmaline: Strategy to combat Alzheimer's disease

Adnan, Mohd; Anwar, Saleha; DasGupta, Debarati; Patel, Mitesh; Elasbali, Abdelbaset Mohamed; Alhassan, Hassan H.; Shafie, Alaa; Siddiqui, Arif Jamal; Bardakçı, Fevzi; Snoussi, Mejdi; Hassan, Md. Imtaiyaz

doi:10.1016/j.ijbiomac.2022.10.115

Cited by 15 publications

(7 citation statements)

References 55 publications

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“…Various synthetic and natural compounds ( Anwar et al, 2020c ; Anwar et al, 2021 ; Anwar et al, 2022d ; Voura et al, 2022 ; Adnan et al, 2023 ) have been used in the past, showing their potential role as MARK4 inhibitors. Anti-AD agents such as donepezil and rivastigmine have also been studied for their mechanistic roles on AD via inhibiting MARK4 activity ( Shamsi et al, 2020b ).…”

Section: Discussionmentioning

confidence: 99%

Mechanistic insights into MARK4 inhibition by galantamine toward therapeutic targeting of Alzheimer’s disease

Adnan,

DasGupta,

Anwar

et al. 2023

Front. Pharmacol.

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Introduction: Hyperphosphorylation of tau is an important event in Alzheimer’s disease (AD) pathogenesis, leading to the generation of “neurofibrillary tangles,” a histopathological hallmark associated with the onset of AD and related tauopathies. Microtubule-affinity regulating kinase 4 (MARK4) is an evolutionarily conserved Ser-Thr (S/T) kinase that phosphorylates tau and microtubule-associated proteins, thus playing a critical role in AD pathology. The uncontrolled neuronal migration is attributed to overexpressed MARK4, leading to disruption in microtubule dynamics. Inhibiting MARK4 is an attractive strategy in AD therapeutics.Methods: Molecular docking was performed to see the interactions between MARK4 and galantamine (GLT). Furthermore, 250 ns molecular dynamic studies were performed to investigate the stability and conformational dynamics of the MARK4–GLT complex. We performed fluorescence binding and isothermal titration calorimetry studies to measure the binding affinity between GLT and MARK4. Finally, an enzyme inhibition assay was performed to measure the MARK4 activity in the presence and absence of GLT.Results: We showed that GLT, an acetylcholinesterase inhibitor, binds to the active site cavity of MARK4 with an appreciable binding affinity. Molecular dynamic simulation for 250 ns demonstrated the stability and conformational dynamics of the MARK4–GLT complex. Fluorescence binding and isothermal titration calorimetry studies suggested a strong binding affinity. We further show that GLT inhibits the kinase activity of MARK4 significantly (IC50 = 5.87 µM).Conclusion: These results suggest that GLT is a potential inhibitor of MARK4 and could be a promising therapeutic target for AD. GLT’s inhibition of MARK4 provides newer insights into the mechanism of GLT’s action, which is already used to improve cognition in AD patients.

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Section: Discussionmentioning

confidence: 99%

Mechanistic insights into MARK4 inhibition by galantamine toward therapeutic targeting of Alzheimer’s disease

Adnan,

DasGupta,

Anwar

et al. 2023

Front. Pharmacol.

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“…Computational methods such as molecular dynamics (MDs) are used to understand how ligands behave in the binding pocket of receptors based on their time-dependent conformational stability. Several studies have demonstrated its practical application in identifying new inhibitors in a number of applications [ 33 , 34 , 35 , 36 ]. In this study, MD analyses were performed with Gromacs version 2019.4 [ 37 ].…”

Section: Methodsmentioning

confidence: 99%

Integrated Network Pharmacology, Molecular Docking, Molecular Simulation, and In Vitro Validation Revealed the Bioactive Components in Soy-Fermented Food Products and the Underlying Mechanistic Pathways in Lung Cancer

Elkhalifa,

Banu,

Khan

et al. 2023

Nutrients

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Globally, lung cancer remains one of the leading causes of cancer-related mortality, warranting the exploration of novel and effective therapeutic approaches. Soy-fermented food products have long been associated with potential health benefits, including anticancer properties. There is still a lack of understanding of the active components of these drugs as well as their underlying mechanistic pathways responsible for their anti-lung cancer effects. In this study, we have undertaken an integrated approach combining network pharmacology and molecular docking to elucidate the mechanism of action of soy-fermented food products against lung cancer through simulation and in vitro validation. Using network pharmacology, we constructed a comprehensive network of interactions between the identified isoflavones in soy-fermented food products and lung cancer-associated targets. Molecular docking was performed to predict the binding affinities of these compounds with key lung cancer-related proteins. Additionally, molecular simulation was utilized to investigate the stability of the compound–target complexes over time, providing insights into their dynamic interactions. Our results identified daidzein as a potential active component in soy-fermented food products with high binding affinities towards critical lung cancer targets. Molecular dynamic simulations confirmed the stability of the daidzein–MMP9 and daidzein–HSP90AA1 complexes, suggesting their potential as effective inhibitors. Additionally, in vitro validation experiments demonstrated that treatment with daidzein significantly inhibited cancer cell proliferation and suppressed cancer cell migration and the invasion of A549 lung cancer cells. Consequently, the estrogen signaling pathway was recognized as the pathway modulated by daidzein against lung cancer. Overall, the findings of the present study highlight the therapeutic potential of soy-fermented food products in lung cancer treatment and provide valuable insights for the development of targeted therapies using the identified bioactive compounds. Further investigation and clinical studies are warranted to validate these findings and translate them into clinical applications for improved lung cancer management.

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“…A further study was undertaken to understand how ligands behave within the binding pocket of receptors as a result of their time-dependent conformational stability, which was based on the MD studies. The usefulness of this method has been demonstrated in several studies, including the identification of new inhibitors in a variety of applications [48][49][50][51]. As part of this study, MD analyses were conducted using GROMACS version 2019.4 [52].…”

Section: Molecular Dynamics Simulationmentioning

confidence: 99%

Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation to Elucidate the Molecular Targets and Potential Mechanism of Phoenix dactylifera (Ajwa Dates) against Candidiasis

Adnan,

Siddiqui,

Ashraf

et al. 2023

Pathogens

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Candidiasis, caused by opportunistic fungal pathogens of the Candida genus, poses a significant threat to immunocompromised individuals. Natural compounds derived from medicinal plants have gained attention as potential sources of anti-fungal agents. Ajwa dates (Phoenix dactylifera L.) have been recognized for their diverse phytochemical composition and therapeutic potential. In this study, we employed a multi-faceted approach to explore the anti-candidiasis potential of Ajwa dates’ phytochemicals. Utilizing network pharmacology, we constructed an interaction network to elucidate the intricate relationships between Ajwa dates phytoconstituents and the Candida-associated molecular targets of humans. Our analysis revealed key nodes in the network (STAT3, IL-2, PTPRC, STAT1, CASP1, ALB, TP53, TLR4, TNF and PPARG), suggesting the potential modulation of several crucial processes (the regulation of the response to a cytokine stimulus, regulation of the inflammatory response, positive regulation of cytokine production, cellular response to external stimulus, etc.) and fungal pathways (Th17 cell differentiation, the Toll-like receptor signaling pathway, the C-type lectin receptor signaling pathway and necroptosis). To validate these findings, molecular docking studies were conducted, revealing the binding affinities of the phytochemicals towards selected Candida protein targets of humans (ALB–rutin (−9.7 kJ/mol), STAT1–rutin (−9.2 kJ/mol), STAT3–isoquercetin (−8.7 kJ/mol), IL2–β-carotene (−8.5 kJ/mol), CASP1–β-carotene (−8.2 kJ/mol), TP53–isoquercetin (−8.8 kJ/mol), PPARG–luteolin (−8.3 kJ/mol), TNF–βcarotene (−7.7 kJ/mol), TLR4–rutin (−7.4 kJ/mol) and PTPRC–rutin (−7.0 kJ/mol)). Furthermore, molecular dynamics simulations of rutin–ALB and rutin-STAT1 complex were performed to gain insights into the stability and dynamics of the identified ligand–target complexes over time. Overall, the results not only contribute to the understanding of the molecular interactions underlying the anti-fungal potential of specific phytochemicals of Ajwa dates in humans but also provide a rational basis for the development of novel therapeutic strategies against candidiasis in humans. This study underscores the significance of network pharmacology, molecular docking and dynamics simulations in accelerating the discovery of natural products as effective anti-fungal agents. However, further experimental validation of the identified compounds is warranted to translate these findings into practical therapeutic applications.

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Targeting inhibition of microtubule affinity regulating kinase 4 by Harmaline: Strategy to combat Alzheimer's disease

Cited by 15 publications

References 55 publications

Mechanistic insights into MARK4 inhibition by galantamine toward therapeutic targeting of Alzheimer’s disease

Mechanistic insights into MARK4 inhibition by galantamine toward therapeutic targeting of Alzheimer’s disease

Integrated Network Pharmacology, Molecular Docking, Molecular Simulation, and In Vitro Validation Revealed the Bioactive Components in Soy-Fermented Food Products and the Underlying Mechanistic Pathways in Lung Cancer

Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation to Elucidate the Molecular Targets and Potential Mechanism of Phoenix dactylifera (Ajwa Dates) against Candidiasis

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