Epidermal Growth Factor Protein Kinase Research Articles

Molecular Docking, HOMO-LUMO, Quantum Chemical Computation and Bioactivity Analysis of vic-Dioxim Derivatives Bearing Hydrazone Group Ligand and Their NiII and CuII Complexes

Molecular docking process was performed to investigate the interactions between the synthesized compounds and human epidermal growth factor protein kinase domain EGFR (PDB ID:1M17) and cyclin-dependent kinase-2 CDK2 (PDB ID:3IG7) proteins. HOMO LUMO orbital energy analysis, quantum chemical calculations were made and the bioactivity parameters of the compounds were evaluated. NiII and CuII complexes of the L1H2 L2H2 and L3H2, ligands showed higher binding affinity to EGFR and CDK2. Especially, [Cu(L1H)2] and [Cu(L2H)2] complexes can be suggested as hit compounds against CDK2 and EGFR, respectively. These were supported by the inhibition constant values which were the lowest when compared to others. L1H2 L2H2 and L3H2, ligands had the lowest binding energy values when compared to metal complexes. Also, [Cu(L2H)2] complex had a high binding energy value against EGFR. [Ni(L2H)2] and [Cu(L2H)2] complexes with EGFR had the highest LE and FQ values and these were found to be in the recommended range. Furthermore, [Cu(L3H)2] had an acceptable FQ value however its LE value was out of range. Besides, [Cu(L2H)2] had a potent and sufficient electrophile ability (acceptor) among other compounds. In conclusion, these compounds may be suitable compounds for further analysis in anti-cancer drug development with low toxic and targeted properties.

Regulation of Inositol 1,4,5-Trisphosphate Receptor-mediated Calcium Release by the Na/K-ATPase in Cultured Renal Epithelial Cells

It is known that the Na/K-ATPase alpha1 subunit interacts directly with inositol 1,4,5-triphosphate (IP(3)) receptors. In this study we tested whether this interaction is required for extracellular stimuli to efficiently regulate endoplasmic reticulum (ER) Ca(2+) release. Using cultured pig kidney LLC-PK1 cells as a model, we demonstrated that graded knockdown of the cellular Na/K-ATPase alpha1 subunit resulted in a parallel attenuation of ATP-induced ER Ca(2+) release. When the knockdown cells were rescued by knocking in a rat alpha1, the expression of rat alpha1 restored not only the cellular Na/K-ATPase but also ATP-induced ER Ca(2+) release. Mechanistically, this defect in ATP-induced ER Ca(2+) release was neither due to the changes in the amount or the function of cellular IP(3) and P2Y receptors nor the ER Ca(2+) content. However, the alpha1 knockdown did redistribute cellular IP(3) receptors. The pool of IP(3) receptors that resided close to the plasma membrane was abolished. Because changes in the plasma membrane proximity could reduce the efficiency of signal transmission from P2Y receptors to the ER, we further determined the dose-dependent effects of ATP on protein kinase Cepsilon activation and ER Ca(2+) release. The data showed that the alpha1 knockdown de-sensitized the ATP-induced ER Ca(2+) release but not PKCepsilon activation. Moreover, expression of the N terminus of Na/K-ATPase alpha1 subunit not only disrupted the formation of the Na/K-ATPase-IP(3) receptor complex but also abolished the ATP-induced Ca(2+) release. Finally, we observed that the alpha1 knockdown was also effective in attenuating ER Ca(2+) release provoked by angiotensin II and epidermal growth factor.