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

Abstract

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.

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

“…The interactions between the hydrophobic native contacts within the enzyme structure is a significant intermolecular interaction that influences enzyme inhibition. Hydrophobic interaction produced among the non-polar residues confirms the stability of the enzyme structure in solution by protecting the non-polar residues inside the hydrophobic core distant from an aqueous solution (Chen & Panagiotopoulos, 2019 ; Gupta et al, 2020 ). As shown in Figure 5A , an average SASA for all the selected compounds has been calculated during the 100 ns MD simulation run.…”

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

“… 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.…”

Dieckol and Its Derivatives as Potential Inhibitors of SARS-CoV-2 Spike Protein (UK Strain: VUI 202012/01): A Computational Study

“…Prime calculates MM-GBSA using the relative binding affinity of protein–ligand without considering any simulation process. Furthermore, previous reports suggest a disagreement between docking Δ G and MM-GBSA Δ G bind determined using Prime module [ 29 , 30 , 31 ]. Many ligands have been shown to bind the RBD of Spike protein with an estimated value of Δ G bind in the range of −21.45 to −54.11 kcal/mol, which is close to our estimated value [ 32 , 33 ].…”