Computational & experimental evaluation of the structure/activity relationship of β-carbolines as DYRK1A inhibitors

Bioorg Med Chem Lett. 2014 Oct 15;24(20):4854-60. doi: 10.1016/j.bmcl.2014.08.054. Epub 2014 Sep 2.

Abstract

DYRK1A has been associated with Down's syndrome and neurodegenerative diseases, therefore it is an important target for novel pharmacological interventions. We combined a ligand-based pharmacophore design with a structure-based protein/ligand docking using the software MOE in order to evaluate the underlying structure/activity relationship. Based on this knowledge we synthesized several novel β-carboline derivatives to validate the theoretical model. Furthermore we identified a modified lead structure as a potent DYRK1A inhibitor (IC50=130 nM) with significant selectivity against MAO-A, DYRK2, DYRK3, DYRK4 & CLK2.

Keywords: DYRK1A; Docking; Inhibitor; MAO-A; Pharmacophore; SAR; β-Carboline.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbolines / chemical synthesis
  • Carbolines / chemistry*
  • Carbolines / pharmacology*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Dyrk Kinases
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Software
  • Structure-Activity Relationship

Substances

  • Carbolines
  • Ligands
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases