2. Academic Validation
  3. Identification of allosteric ERK2 inhibitors through in silico biased screening and competitive binding assay

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

Affiliations

  • 1 Graduate School of Science, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan. Electronic address: kinotk@b.s.osakafu-u.ac.jp.
  • 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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