Discovery of potent small molecule inhibitors of DYRK1A by structure-based virtual screening and bioassay

Bioorg Med Chem Lett. 2012 Jan 1;22(1):168-71. doi: 10.1016/j.bmcl.2011.11.043. Epub 2011 Nov 18.

Abstract

In this study, six novel dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) inhibitors with IC(50) values ranging from 1.51 to 88.13 μM were successfully identified through virtual screening and in vitro plus cell based bioassay. Compound 5 with IC(50) value of 1.51 μM is the most potent hit against DYRK1A in vitro, while compound 3 exhibited the most potent activity in cultured cells. The inhibition mechanism was explored by molecular docking approach. This study may provide a start point for further mechanism based study as well as discovery of drug candidate against Down syndrome (DS).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Animals
  • Biochemistry / methods
  • Biological Assay / methods*
  • Chemistry, Pharmaceutical / methods*
  • Dose-Response Relationship, Drug
  • Down Syndrome / drug therapy*
  • Drug Design
  • Humans
  • In Vitro Techniques
  • Inhibitory Concentration 50
  • Mice
  • Mice, Transgenic
  • Models, Chemical
  • Neurodegenerative Diseases / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*

Substances

  • Adenosine Triphosphate
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases