Implications of tempol in pyruvate dehydrogenase kinase 3 targeted anticancer therapeutics: Computational, spectroscopic, and calorimetric studies

Anwar, Saleha; DasGupta, Debarati; Shafie, Alaa; Alhumaydhi, Fahad A.; Alsagaby, Suliman A.; Shahwan, Moyad; Anjum, Farah; Abdulmonem, Waleed Al; Sharaf, Sharaf E; Hassan, Md. Imtaiyaz

doi:10.1016/j.molliq.2022.118581

Cited by 19 publications

(15 citation statements)

References 63 publications

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“…The docking was performed using InstaDock [ 28 ] where search space was defined as −39.46, −14.339, and −1.963 with sizes 50, 70, and 80 for X, Y, and Z coordinates, respectively. All other conditions and parameters were followed as per earlier published literature [ 29 , 30 ].…”

Section: Methodsmentioning

confidence: 99%

“…To obtain the parameters of the ligand (Mtf), we performed the geometry optimization of the fragment using the B3LYP/6-31G(d) method in the Gaussian 16 program [ 31 ]. All other conditions and parameters were followed as per earlier published literature [ 29 , 30 ].…”

Section: Methodsmentioning

confidence: 99%

“…A five step equilibration was set up, gradually dialling down the harmonic restraints on the protein backbone from 5, 2, 1, 0.1 kcal/mol Å 2 ; at last step there was no limitation. All other conditions and parameters were followed as per earlier published literature [ 29 , 30 ].…”

Section: Methodsmentioning

confidence: 99%

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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: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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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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“…The binding affinities of fluoxetine, memantine, and galantamine with irisin were investigated using a VP-ITC microcalorimeter (MicroCal, Inc, GE, MicroCal, Northampton, MA, USA) at 25 °C following previously published reports [ 41 ]. The sample cell was filled with irisin solution while the three ligands were loaded into the rotator syringe.…”

Section: Methodsmentioning

confidence: 99%

Unraveling the Binding Mechanism of Alzheimer’s Drugs with Irisin: Spectroscopic, Calorimetric, and Computational Approaches

Waseem

Shamsi

Khan

et al. 2022

IJMS

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The prevalence of Alzheimer’s disease (AD) has been a major health concern for a long time. Despite recent progress, there is still a strong need to develop effective disease-modifying therapies. Several drugs have already been approved to retard the progression of AD-related symptoms; however, there is a need to develop an effective carrier system for the delivery of drugs to combat such diseases. In recent years, various biological macromolecules, including proteins, have been used as carriers for drug delivery. Irisin is a beneficial hormone in such diseases, including AD and related pathologies. Herein, the interaction mechanism of irisin with AD drugs such as memantine, galantamine, and fluoxetine is investigated. Fluorescence studies revealed that the above drugs bind to irisin with significant affinity, with fluoxetine having the highest binding affinity. Isothermal titration calorimetry (ITC) complemented the spontaneous binding of these drugs with irisin, delineating various associated thermodynamic and binding parameters. Molecular docking further validated the fluorescence and ITC results and unfolded the mechanism that hydrogen bonding governs the binding of fluoxetine to irisin with a significant binding score, i.e., −6.3 kcal/mol. We believe that these findings provide a promising solution to fight against AD as well as a platform for further research to utilize irisin in the drug-delivery system for an effective therapeutic strategy.

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“…Natural products are extensively used to target cancer therapy with minimal side effects ( Anwar et al, 2020a ; Anwar et al, 2020b ; Anjum et al, 2021 ; Anwar et al, 2021 ; Anwar et al, 2022a ; Anwar et al, 2022b ; Anwar et al, 2022c ). Cinnamomum zeylanicum (CZ) is a tropical evergreen plant belonging to the genus Cinnamomum.…”

Section: Introductionmentioning

confidence: 99%

Cinnamomum zeylanicum Extract and its Bioactive Component Cinnamaldehyde Show Anti-Tumor Effects via Inhibition of Multiple Cellular Pathways

et al. 2022

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Cinnamomum zeylanicum is a tropical plant with traditional medicinal significance that possesses antimicrobial, antifungal, anti-parasitic, and anti-tumor properties. Here, we have elucidated the anti-tumor effects of Cinnamomum zeylanicum extract (CZE) and its bioactive compound cinnamaldehyde (CIN) on oral cancer and elucidated underlying molecular mechanisms. Anti-tumor activities of CZE and CIN were demonstrated by various in vitro experiments on oral cancer cells (SCC-4, SCC-9, SCC-25). The cell proliferation, growth, cell cycle arrest, apoptosis, and autophagy were analyzed by MTT, clonogenic assay, propidium iodide, annexin-V-PI, DAPI, and acridine orange staining, respectively. The binding affinity of CIN towards dihydrofolate reductase and p38-MAP kinase alpha was analyzed by molecular docking. Western blot assay was performed to assess the alteration in the expression of various proteins. CZE and CIN treatment significantly inhibited the growth and proliferation of oral cancer cells in a dose-dependent manner. These treatments further induced apoptosis, cell cycle arrest, and autophagy. CZE and CIN inhibited the invasion and cytoplasmic translocation of NF-κB in these cell lines. CIN showed a high affinity to MAP kinase P38 alpha and dihydrofolate reductase with binding affinities of −6.8 and −5.9 kcal/mol, respectively. The cancer cells showed a decreased expression of various PI3k-AKT-mTOR pathways related to VEGF, COX-2, Bcl-2, NF-κB, and proteins post-treatment.

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Implications of tempol in pyruvate dehydrogenase kinase 3 targeted anticancer therapeutics: Computational, spectroscopic, and calorimetric studies

Cited by 19 publications

References 63 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

Unraveling the Binding Mechanism of Alzheimer’s Drugs with Irisin: Spectroscopic, Calorimetric, and Computational Approaches

Cinnamomum zeylanicum Extract and its Bioactive Component Cinnamaldehyde Show Anti-Tumor Effects via Inhibition of Multiple Cellular Pathways

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