Molecular interaction studies on ellagic acid for its anticancer potential targeting pyruvate dehydrogenase kinase 3

Dahiya, Rashmi; Mohammad, Taj; Gupta, Preeti; Haque, Anzarul; Alajmi, Mohamed F.; Hussain, Afzal; Hassan, Md. Imtaiyaz

doi:10.1039/c9ra02864a

Cited by 46 publications

(26 citation statements)

References 86 publications

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“…The anti-carcinogenic, anti-angiogenic and anti-inflammatory effects of both of these dietary phytochemicals has been well established in the literature 73–78 . Recently, we have observed that quercetin and ellagic acid shows an excellent binding affinity to the pyruvate dehydrogenase kinase 3 and inhibits its enzyme activity 79,80 .…”

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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show abstract

“…To understand the physical basis of the structure and function of biological macromolecules, MD simulation substantiates to be an essential approach (Amir et al, 2020 ; Beg et al, 2019 ; Dahiya et al, 2019 ; Gulzar et al, 2019 ; Gupta et al, 2019 ; Gupta et al, 2019 ). This technique assists in discovering the structural dynamics and how it is coupled to the biomolecular function of the enzyme (McCammon et al, 1977 ; Karplus & McCammon, 2002 ; Arnittali et al, 2019 ).…”

Section: Methodsmentioning

confidence: 99%

Structure-based identification of potential SARS-CoV-2 main protease inhibitors

Khan

Fakhar

Hussain

et al. 2020

Journal of Biomolecular Structure and Dynamics

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“…The titration data were further analyzed using MicroCal Origin 7.0. The binding isotherm was fitted with a binding site model for determination of association constant ( K a ), enthalpy change (Δ H ), and entropy change (Δ S ) as described [ 75 , 76 ].…”

Section: Methodsmentioning

confidence: 99%

Design and Development of Novel Urea, Sulfonyltriurea, and Sulfonamide Derivatives as Potential Inhibitors of Sphingosine Kinase 1

et al. 2020

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Sphingosine kinase 1 (SphK1) is one of the well-studied drug targets for cancer and inflammatory diseases. Recently discovered small-molecule inhibitors of SphK1 have been recommended in cancer therapeutics; however, selectivity and potency of first-generation inhibitors are great challenge. In search of effective SphK1 inhibitors, a set of small molecules have been designed and synthesized bearing urea, sulfonylurea, sulfonamide, and sulfonyltriurea groups. The binding affinity of these inhibitors was measured by fluorescence-binding assay and isothermal titration calorimetry. Compounds 1, 5, 6, and 7 showed an admirable binding affinity to the SphK1 in the sub-micromolar range and significantly inhibited SphK1 activity with admirable IC50 values. Molecular docking studies revealed that these compounds fit well into the sphingosine binding pocket of SphK1 and formed significant number of hydrogen bonds and van der Waals interactions. These molecules may be exploited as potent and selective inhibitors of SphK1 that could be implicated in cancer therapeutics after the required in vivo validation.

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Molecular interaction studies on ellagic acid for its anticancer potential targeting pyruvate dehydrogenase kinase 3

Abstract: PDK3 plays a central role in cancer through the reversible phosphorylation of PDC thereby blocking the entry of pyruvate into the TCA cycle. PDK3 mediated metabolic switching can be therapeutically targeted for glycolysis addicted cancers.

Cited by 46 publications

References 86 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

Structure-based identification of potential SARS-CoV-2 main protease inhibitors

Design and Development of Novel Urea, Sulfonyltriurea, and Sulfonamide Derivatives as Potential Inhibitors of Sphingosine Kinase 1

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