Hajime Sugiyama, Mayu Yoshida, Haruna Nagao, Masaaki Sawa, Takayoshi Kinoshita
Bioorganic & medicinal chemistry letters 2023 Sep 01Extracellular 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. Copyright © 2023 Elsevier Ltd. All rights reserved.
Hajime Sugiyama, Mayu Yoshida, Haruna Nagao, Masaaki Sawa, Takayoshi Kinoshita. Low entropic cost of binding confers high selectivity on an allosteric ERK2 inhibitor. Bioorganic & medicinal chemistry letters. 2023 Sep 01;93:129431
PMID: 37544371
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