Low entropic cost of binding confers high selectivity on an allosteric ERK2 inhibitor.
Bioorg Med Chem Lett
; 93: 129431, 2023 09 01.
Article
em En
| MEDLINE
| ID: mdl-37544371
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteína Quinase 1 Ativada por Mitógeno
/
Diabetes Mellitus Tipo 2
Tipo de estudo:
Health_economic_evaluation
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article