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.
Takayoshi Kinoshita  1 ,  Hajime Sugiyama  2 ,  Yurika Mori  3 ,  Naruhide Takahashi  3 ,  Atsushi Tomonaga  2
Affiliations
  • 1. Graduate School of Science, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan. Electronic address: [email protected].
  • 2. Next Generation Healthcare Innovation Center, Fujitsu Limited, 17-25, Shinkamata 1-chome, Ota-ku, Tokyo, Tokyo 144-8588, Japan.
  • 3. Graduate School of Science, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.
PMID: 26733474 DOI: 10.1016/j.bmcl.2015.12.056
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.
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