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

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. Copyright © 2023 Elsevier Ltd. All rights reserved.

Citation

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

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PMID: 37544371

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