IKK-beta inhibitors: an analysis of drug-receptor interaction by using molecular docking and pharmacophore 3D-QSAR approaches

J Mol Graph Model. 2010 Aug 24;29(1):72-81. doi: 10.1016/j.jmgm.2010.04.008. Epub 2010 May 10.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / chemistry
  • Models, Molecular*
  • Molecular Sequence Data
  • Protein Kinase Inhibitors / metabolism*
  • Protein Kinase Inhibitors / pharmacology*
  • Quantitative Structure-Activity Relationship*
  • Receptors, Drug / metabolism*
  • Structural Homology, Protein

Substances

  • Protein Kinase Inhibitors
  • Receptors, Drug
  • I-kappa B Kinase