Identification of allosteric ERK2 inhibitors through in silico biased screening and competitive binding assay

Bioorg Med Chem Lett. 2016 Feb 1;26(3):955-958. doi: 10.1016/j.bmcl.2015.12.056. Epub 2015 Dec 18.

Abstract

Extracellular signal-regulated kinase 2 (ERK2) is a drug target for type 2 diabetes mellitus. A peptide-type ERK2 inhibitor (PEP) was discovered in the previous study through the knowledge-based method and showed physiological effects on the db/db mice model of type 2 diabetes. Here, the crystal structure showed that PEP bound to the allosteric site without the interruption of the ATP competitive inhibitor binding to ERK2. An in silico biased-screening using the focused library rendered three compounds with inhibitory activity of IC50 <100 μM. Among them, two compounds revealed the concentration-dependent competition with PEP and could be lead compounds for antidiabetic medicine.

Keywords: Allosteric inhibitor; Competitive binding assay; Crystal structure; ERK2; In silico screening.

MeSH terms

  • Allosteric Site
  • Animals
  • Binding Sites
  • Binding, Competitive
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / pathology
  • Disease Models, Animal
  • Drug Design
  • Inhibitory Concentration 50
  • Mice
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Structure, Tertiary

Substances

  • Protein Kinase Inhibitors
  • Mitogen-Activated Protein Kinase 1