Abstract
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•Inhibitory potential of ellagic acid to SphK1 was evaluated using molecular docking, binding and kinase inhibition studies.•Ellagic acid shows excellent binding affinity to SphK1 and significantly reduces its catalytic activity.•Ellagic acid binds to ATP-binding pocket of SphK1 through various stabilizing interactions.•Ellagic acid forms stable complex with SphK1 without any significant conformational switch in native protein structure.•EA is potentially lethal to the cancerous cells whereas non-toxic to the normal cells.
Sphingosine kinase 1 (SphK1) is one of the central enzymes of sphingolipid metabolism whose high expression level is presumed to be correlated with cancer and other inflammatory diseases. Using a virtual screening approach and in vitro studies, we have identified the ellagic acid (EA), a dietary polyphenol, as a potent inhibitor of SphK1. Molecular docking study has suggested a strong binding affinity of EA to the SphK1. Fluorescence binding and isothermal titration calorimetry (ITC) measurements has also indicated an appreciable binding affinity. Kinase inhibition assay revealed an excellent inhibitory action of EA towards SphK1 (IC50 = 0.74 ± 0.06 μM). Cell viability studies point towards the antiproliferative effects of EA on lung cancer cell line (A549) without affecting human embryonic kidney cells (HEK293). Binding and inhibition mechanism of EA was unveiled by docking analysis of SphK1-EA complex. EA binds to the SphK1 and forms several interactions with catalytically important residues of ATP-binding pocket. Structural stability and dynamics analysis of SphK1-EA complex during 100 ns molecular dynamic simulation studies suggested that EA forms a stable complex with SphK1 without inducing any significant conformational shift. Taken together, our study suggests that EA can be utilized as a chemical prototype to develop potent therapeutics targeting SphK1-associated pathologies.