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

Abstract

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.

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

“…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 ).…”

Identification of High-Affinity Inhibitors of Cyclin-Dependent Kinase 2 Towards Anticancer Therapy

“…Final MD run was performed for 50,000 ps for both systems and the resulting trajectory was analyzed using inbuilt utilities of the GROMACS. The details of MD simulations have been described in our previous research [54,55].…”

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

“…To further evaluate the inhibitory potential and to calculate the IC 50 values of the compounds’ hits revealed from initial screening, an enzymatic assay of SphK1 was performed across a narrower range (0–35 μM). The ATPase activity of SphK1 was quantified in terms of hydrolyzed phosphate in picomolar concentration using a phosphate standard curve as described [ 62 , 63 ]. The decrease in the activity of SphK1 was plotted in terms of percentage inhibition against an increasing dose of respective compounds, which revealed IC 50 values in the micromolar range ( Figure 7 , Table 3 ).…”