2. Academic Validation
  3. Low entropic cost of binding confers high selectivity on an allosteric ERK2 inhibitor

Low entropic cost of binding confers high selectivity on an allosteric ERK2 inhibitor

  • Bioorg Med Chem Lett. 2023 Sep 1:93:129431. doi: 10.1016/j.bmcl.2023.129431.
Hajime Sugiyama 1,  Mayu Yoshida 2,  Haruna Nagao 3,  Masaaki Sawa 3,  Takayoshi Kinoshita 4
Affiliations

Affiliations

  • 1 Mitsubishi Chemical Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-8502, Japan.
  • 2 Graduate School of Science, Osaka Metropolitan University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.
  • 3 Carna Biosciences, Inc., 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
  • 4 Graduate School of Science, Osaka Metropolitan University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan. Electronic address: kinotk@omu.ac.jp.
PMID: 37544371 DOI: 10.1016/j.bmcl.2023.129431
Abstract

Extracellular signal-regulated kinase 2 (ERK2), a mitogen-activated protein kinase (MAPK), plays an essential role in physiological cellular processes and is a drug target for treating cancers and type 2 diabetes. A previous in silico screening study focusing on an allosteric site that plays a crucial role in substrate anchoring conferred an ERK2 Inhibitor (compound 1). In this report, compound 1 was found to show high selectivity toward ERK2 compared with the nearest off-target p38α MAPK, and the crystal structure revealed that compound 1 binds to the allosteric site of ERK2. Fragment molecular orbital calculations based upon this crystal structure provided the structural basis to improve potency of compound 1 derivatives. Further computational studies uncovered that the low entropic cost of binding conferred the high selectivity of compound 1 toward ERK2 over p38α MAPK. These findings demonstrate the feasibility of developing potent and selective ERK2 inhibitors.

Keywords

Allosteric inhibitor; Cancer; Computational chemistry; ERK2; Selectivity; X-ray crystal structure.

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