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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.

The sphingosine kinase-1/sphingosine-1-phosphate pathway is linked with the cancer progression and survival of the chemotherapy-challenged cells. Sphingosine kinase-1 (SphK1) has emerged as an attractive drug target, but their inhibitors from natural sources are limited. In this study, we have chosen harmaline, one of the β-carboline alkaloids, and report its mechanism of binding to SphK1 and subsequent inhibition. Molecular docking combined with fluorescence binding studies revealed that harmaline binds to the substrate-binding pocket of SphK1 with an appreciable binding affinity and significantly inhibits the kinase activity of SphK1 with an IC 50 value in the micromolar range. The cytotoxic effect of harmaline on non-small-cell lung cancer cells by MTT assay was found to be higher for H1299 compared to A549. Harmaline induces apoptosis in non-small-cell lung carcinoma cells (H1299 and A549), possibly via the intrinsic pathway. Our findings suggest that harmaline could be implicated as a scaffold for designing potent anticancer molecules with SphK1 inhibitory potential.

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.

Sphingosine kinase 1 (SphK1) has emerged as an attractive drug target for different diseases. Recently, discovered SphK1 inhibitors have been recommended in cancer therapeutics; however, selectivity and potency are great challenges. In this study, a novel series of benzimidazoles was synthesized and evaluated as SphK1 inhibitors. Our design strategy is twofold: It aimed first to study the effect of replacing the 5‐position of the benzimidazole ring with a polar carboxylic acid group on the SphK1‐inhibitory activity and cytotoxicity. Our second aim was to optimize the structures of the benzimidazoles through the elongation of the chain. The enzyme inhibition potentials against all the synthesized compounds toward SphK1 were evaluated, and the results revealed that most of the studied compounds inhibited SphK1 effectively. The binding affinity of the benzimidazole derivatives toward SphK1 was measured by fluorescence binding and molecular docking. Compounds 33, 37, 39, 41, 42, 43, and 45 showed an appreciable binding affinity. Therefore, the SphK1‐inhibitory potentials of compounds 33, 37, 39, 41, 42, 43, and 45 were studied and IC50 values were determined, to reveal high potency. The study showed that these compounds inhibited SphK1 with effective IC50 values. Among the studied compounds, compound 41 was the most effective one with the lowest IC50 value and a high cytotoxicity on a wide spectrum of cell lines. Molecular docking revealed that most of these compounds fit well into the ATP‐binding site of SphK1 and form hydrogen bond interactions with catalytically important residues. Overall, the findings suggest the therapeutic potential of benzimidazoles in the clinical management of SphK1‐associated diseases.

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