Design and Synthesis of Novel Protein Kinase R (PKR) Inhibitors

Mol Divers. 2016 Nov;20(4):805-819. doi: 10.1007/s11030-016-9689-4. Epub 2016 Aug 1.

Abstract

Protein kinase RNA-activated (PKR) plays an important role in a broad range of intracellular regulatory mechanisms and in the pathophysiology of many human diseases, including microbial and viral infections, cancer, diabetes and neurodegenerative disorders. Recently, several potent PKR inhibitors have been synthesized. However, the enzyme's multifunctional character and a multitude of PKR downstream targets have prevented the successful transformation of such inhibitors into effective drugs. Thus, the need for additional PKR inhibitors remains. With the help of computer-aided drug-discovery tools, we designed and synthesized potential PKR inhibitors. Indeed, two compounds were found to inhibit recombinant PKR in pharmacologically relevant concentrations. One compound, 6-amino-3-methyl-2-oxo-N-phenyl-2,3-dihydro-1H-benzo[d]imidazole-1-carboxamide, also showed anti-apoptotic properties. The novel molecules diversify the existing pool of PKR inhibitors and provide a basis for the future development of compounds based on PKR signal transduction mechanism.

Keywords: Benzoimidazole derivatives; C16; Computer modelling; PKR inhibitors.

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Drug Design*
  • Models, Molecular*
  • Molecular Conformation
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Quantitative Structure-Activity Relationship
  • eIF-2 Kinase / antagonists & inhibitors
  • eIF-2 Kinase / chemistry*

Substances

  • Protein Kinase Inhibitors
  • eIF-2 Kinase