Elucidation of interaction mechanism of ellagic acid to the integrin linked kinase

Gulzar, M. Saeed; Syed, Sunayana Begum; Khan, Faez Iqbal; Κhan, Parvez; Ali, Shahid; Hasan, Gulam Mustafa; Taneja, Pankaj; Hassan, Md. Imtaiyaz

doi:10.1016/j.ijbiomac.2018.09.089

Cited by 39 publications

(21 citation statements)

References 56 publications

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“…The aberrant activation of signalling cascades is a frequent event in various types of human cancers 64,65 . Since protein and lipid kinases are key members of almost all signalling pathways, developing anticancer therapies targeting these central enzymes has always been a matter of choice among researchers 66–68 . To this end, SphK1 has emerged as a key enzyme as it regulates the sphingolipid rheostat responsible for determining cell fate.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of binding and inhibition mechanism of dietary phytochemicals with sphingosine kinase 1: Towards targeted anticancer therapy

Gupta

Mohammad

Dahiya

et al. 2019

Sci Rep

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Sphingosine kinase 1 (SphK1) has recently gained attention as a potential drug target for its association with cancer and other inflammatory diseases. Here, we have investigated the binding affinity of dietary phytochemicals viz., ursolic acid, capsaicin, DL-α tocopherol acetate, quercetin, vanillin, citral, limonin and simvastatin with the SphK1. Docking studies revealed that all these compounds bind to the SphK1 with varying affinities. Fluorescence binding and isothermal titration calorimetric measurements suggested that quercetin and capsaicin bind to SphK1 with an excellent affinity, and significantly inhibits its activity with an admirable IC50 values. The binding mechanism of quercetin was assessed by docking and molecular dynamics simulation studies for 100 ns in detail. We found that quercetin acts as a lipid substrate competitive inhibitor, and it interacts with important residues of active-site pocket through hydrogen bonds and other non-covalent interactions. Quercetin forms a stable complex with SphK1 without inducing any significant conformational changes in the protein structure. In conclusion, we infer that quercetin and capsaicin provide a chemical scaffold to develop potent and selective inhibitors of SphK1 after required modifications for the clinical management of cancer.

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Section: Discussionmentioning

confidence: 99%

Evaluation of binding and inhibition mechanism of dietary phytochemicals with sphingosine kinase 1: Towards targeted anticancer therapy

Gupta

Mohammad

Dahiya

et al. 2019

Sci Rep

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“…Most of the protein kinase inhibitors isolated from plants are polyphenols, mainly belonging to flavonoids [ 19 – 21 , 27 , 28 ]. However, there are representatives of nonflavonoids also that show inhibitory effects for human kinases, including resveratrol, caffeic acid, and gallic acid [ 29 , 30 ]. Our previous studies demonstrated the binding and inhibition of CaMKIV by various natural compounds including hesperidin, β -carotene, and vanillin [ 31 – 33 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of Potential Inhibitors of Calcium/Calmodulin-Dependent Protein Kinase IV from Bioactive Phytoconstituents

Gupta

Khan

Fakhar

et al. 2020

Oxidative Medicine and Cellular Longevity

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Calcium/calmodulin-dependent protein kinase IV (CaMKIV) is an upstream regulator of CaMKK-CaMKIV signaling cascade that activates various transcription factors, thereby regulating several cellular activities including, neuronal communication and immune response. Owing to the abnormal expression in cancer and neurodegenerative diseases, the CaMKIV has been considered a potential drug target. In the present study, we checked the binding affinity of plant-derived natural compounds viz., quercetin, ellagic acid (EA), simvastatin, capsaicin, ursolic acid, DL-α-tocopherol acetate, and limonin towards CaMKIV. Molecular docking and fluorescence binding studies showed that EA and quercetin bind to the CaMKIV with a considerable affinity in comparison to other compounds. Enzyme inhibition assay revealed that both EA and quercetin inhibit CaMKIV activity with their IC50 values in the micromolar range. To get atomistic insights into the mode of interactions, inhibition mechanism, and the stability of the CaMKIV-ligand complex, a 100 ns MD simulation analysis was performed. Both EA and quercetin bind to the catalytically important residues of active site pocket of CaMKIV forming enough stabilizing interactions presumably inhibiting enzyme activity. Moreover, no significant structural change in the CaMKIV was observed upon binding of EA and quercetin. In conclusion, this study illustrates the application of phytoconstituents in the development of therapeutic molecules targeting CaMKIV having implications in cancer and neurodegenerative diseases after in vivo validation.

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“… 19 In recent years, there is a switch in the screening and discovery of natural products as potential kinase inhibitors. 25 , 28 − 31 Plant-derived products have several important biological properties such as antioxidant, anticancerous, anti-inflammatory, antidiabetic, antimicrobial, and hepatoprotective 24 , 25 , 32 and thus are used in treating cancer. One such class of compound is natural polyphenols like flavonoids, which are widely distributed in plants and are generally present in food like herbs, nuts, vegetables, fruits, plant-derived beverages like tea, coffee, and red wine.…”

Section: Introductionmentioning

confidence: 99%

Inhibiting CDK6 Activity by Quercetin Is an Attractive Strategy for Cancer Therapy

et al. 2020

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Cyclin-dependent kinase 6 (CDK6) is a potential drug target that plays an important role in the progression of different types of cancers. We performed in silico and in vitro screening of different natural compounds and found that quercetin has a high binding affinity for the CDK6 and inhibits its activity with an IC 50 = 5.89 μM. Molecular docking and a 200 ns whole atom simulation of the CDK6-quercetin complex provide insights into the binding mechanism and stability of the complex. Binding parameters ascertained by fluorescence and isothermal titration calorimetry studies revealed a binding constant in the range of 10 7 M –1 of quercetin to the CDK6. Thermodynamic parameters associated with the formation of the CDK6–quercetin complex suggested an electrostatic interaction-driven process. The cell-based protein expression studies in the breast (MCF-7) and lung (A549) cancer cells revealed that the treatment of quercetin decreases the expression of CDK6. Quercetin also decreases the viability and colony formation potential of selected cancer cells. Moreover, quercetin induces apoptosis, by decreasing the production of reactive oxygen species and CDK6 expression. Both in silico and in vitro studies highlight the significance of quercetin for the development of anticancer leads in terms of CDK6 inhibitors.

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Elucidation of interaction mechanism of ellagic acid to the integrin linked kinase

Cited by 39 publications

References 56 publications

Evaluation of binding and inhibition mechanism of dietary phytochemicals with sphingosine kinase 1: Towards targeted anticancer therapy

Evaluation of binding and inhibition mechanism of dietary phytochemicals with sphingosine kinase 1: Towards targeted anticancer therapy

Identification of Potential Inhibitors of Calcium/Calmodulin-Dependent Protein Kinase IV from Bioactive Phytoconstituents

Inhibiting CDK6 Activity by Quercetin Is an Attractive Strategy for Cancer Therapy

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