title: Identification of allosteric ERK2 inhibitors through in silico biased screening and competitive binding assay.
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.
authors.affiliation: 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.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kinoshita
authors.affiliation: Next Generation Healthcare Innovation Center, Fujitsu Limited, 17-25, Shinkamata 1-chome, Ota-ku, Tokyo, Tokyo 144-8588, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Sugiyama
authors.affiliation: Graduate School of Science, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.
authors.forename: Yurika
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Graduate School of Science, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.
authors.forename: Naruhide
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Next Generation Healthcare Innovation Center, Fujitsu Limited, 17-25, Shinkamata 1-chome, Ota-ku, Tokyo, Tokyo 144-8588, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tomonaga
mesh_terms: D000495:Allosteric Site; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D015195:Drug Design; D020128:Inhibitory Concentration 50; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D017434:Protein Structure, Tertiary
chemical_list: D047428:Protein Kinase Inhibitors; D019950:Mitogen-Activated Protein Kinase 1
keywords: Allosteric inhibitor; Competitive binding assay; Crystal structure; ERK2; In silico screening