IKK-beta inhibitors: an analysis of drug-receptor interaction by using molecular docking and pharmacophore 3D-QSAR approaches.
The IKK kinases family represents a thrilling area of research because of its importance in regulating the activity of NF-kB transcription factors. The discovery of the central role played by IKK-beta in the activation of transcription in response to apoptotic or inflammatory stimuli allowed to considerate its modulation as a promising tool for the treatment of chronic inflammation and cancer. To date, several IKK-beta inhibitors have been discovered and tested. In this work, an analysis of the interactions between different classes of inhibitors and their biological target was performed, through the application of Molecular Docking and Pharmacophore/3D-QSAR approaches to a set of 141 inhibitors included in the Binding Database. In order to overcome the difficulty due to the lack of crystallographic data for IKK-beta, a homology model of this protein has been built and validated. The results allowed to study in depth the structural bases for the interaction of each family of inhibitors and provided clues for further modifications, with the aim of improving the activity and selectivity of designed drugs targeting this enzyme.
Lauria
Antonino
A
Dipartimento Farmacochimico, Tossicologico e Biologico, Università di Palermo, Via Archirafi 32, Palermo, Italy. lauria@unipa.it
Ippolito
Mario
M
Fazzari
Marco
M
Tutone
Marco
M
Di Blasi
Francesco
F
Mingoia
Francesco
F
Almerico
Anna Maria
AM
D000595:Amino Acid Sequence; D001665:Binding Sites; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D047428:Protein Kinase Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D011955:Receptors, Drug / Q000378:metabolism*; D040681:Structural Homology, Protein
D047428:Protein Kinase Inhibitors; D011955:Receptors, Drug; D051550:I-kappa B Kinase