Protein kinasesfamily plays pivotal roles in nearly every aspectof cellular function. They control metabolism, transcription, cell division and programmed cell death through modification of the protein target function. Typically, the reaction catalyzed by protein kinaseis MgATP1- + protein-O: H -> protein-O: PO32- + MgADP + H+.Protein kinases family has becomeone of the most important drug targets over the past two decades.In particular, most of the FDA-approved protein kinase inhibitors are competitive with respect to ATP. IKK?/?is a member of the protein kinase family and has a central role in NF-?B activationin response to different pro-inflammatory stimuli, since the active form of the enzyme leads to IkB?/?phosphorylation and ultimately to the activation of NF-?B.Our data suggest that ferulic acid (FA) may interfere with IKK/I?B/NF-?B signalling, both reducing NF-?B nuclear translocation and the phosphorylation of IKK?/? and IkB? in LPS-induced Raw 264.7 cells.The regulatory mechanisms governing this phosphorylation event are not well understood. It is known that the molecular mechanism underlying the inhibition of kinase proteins consists of the formation of a ligand-receptor complex. In support, of these experimental outcomes we carried out computational studies by means of Molecular Docking and Induced Fit Docking (IFD) protocols, in order to get new insights at molecular level on the interaction between FA and the human IKK-? (PDB: 4KIK). Furthermore, to better understand the binding mode and the molecular pose, we selected some IKK-beta known ligands such as Staurosporine and BMS 345541, both known as potent ATPase competitors, and also ATP. These studies permitted us to get the preliminary binding affinity on IKK-beta of all the analysed ligands.
In silico insights and molecular characterization between IKK kinase and some ligands
F Mingoia;
2015
Abstract
Protein kinasesfamily plays pivotal roles in nearly every aspectof cellular function. They control metabolism, transcription, cell division and programmed cell death through modification of the protein target function. Typically, the reaction catalyzed by protein kinaseis MgATP1- + protein-O: H -> protein-O: PO32- + MgADP + H+.Protein kinases family has becomeone of the most important drug targets over the past two decades.In particular, most of the FDA-approved protein kinase inhibitors are competitive with respect to ATP. IKK?/?is a member of the protein kinase family and has a central role in NF-?B activationin response to different pro-inflammatory stimuli, since the active form of the enzyme leads to IkB?/?phosphorylation and ultimately to the activation of NF-?B.Our data suggest that ferulic acid (FA) may interfere with IKK/I?B/NF-?B signalling, both reducing NF-?B nuclear translocation and the phosphorylation of IKK?/? and IkB? in LPS-induced Raw 264.7 cells.The regulatory mechanisms governing this phosphorylation event are not well understood. It is known that the molecular mechanism underlying the inhibition of kinase proteins consists of the formation of a ligand-receptor complex. In support, of these experimental outcomes we carried out computational studies by means of Molecular Docking and Induced Fit Docking (IFD) protocols, in order to get new insights at molecular level on the interaction between FA and the human IKK-? (PDB: 4KIK). Furthermore, to better understand the binding mode and the molecular pose, we selected some IKK-beta known ligands such as Staurosporine and BMS 345541, both known as potent ATPase competitors, and also ATP. These studies permitted us to get the preliminary binding affinity on IKK-beta of all the analysed ligands.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.