Discovery of a highly specific and efficacious inhibitor of human carboxylesterase 2 by large-scale screening.
Int J Biol Macromol
; 137: 261-269, 2019 Sep 15.
Article
em En
| MEDLINE
| ID: mdl-31260759
ABSTRACT
Human carboxylesterase 2 (CES2A), one of the most abundant hydrolases distributed in human small intestine and colon, play key roles in the hydrolysis of a wide range of prodrugs and other esters. Recent studies have demonstrated that CES2A inhibitors may ameliorate irinotecan-induced severe diarrhea, but the specific and efficacious inhibitors targeting intracellular CES2A are rarely reported. Herein, a large-scale screening campaign was conducted for discovery of potent and specific CES2A inhibitor(s). Following screening of more than one hundred of natural products, glabridin (a bioactive compound of Glycyrrhiza glabra L.) was found displaying potent inhibition on CES2A and high specificity over CES1A (>500-fold) and other serine hydrolases. Further investigation showed that glabridin was cell permeable and low cytotoxic, as well as capable of inhibiting intracellular CES2A in living cells, with the IC50 value of 0.52⯵M. Molecular dynamics simulations showed that glabridin formed strong and stable interactions with both the catalytic cavity and Z site of CES2A via hydrophobic interactions. In summary, glabridin was a potent and specific inhibitor targeting intracellular CES2A, which could be used as an ideal lead compound to develop more efficacious CES2A inhibitors for modulating the pharmacokinetic behaviors of CES2A-substrate drugs and alleviating irinotecan-induced diarrhea.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
3_ND
Base de dados:
MEDLINE
Assunto principal:
Carboxilesterase
/
Inibidores Enzimáticos
/
Descoberta de Drogas
/
Ensaios de Triagem em Larga Escala
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Limite:
Humans
Idioma:
En
Revista:
Int J Biol Macromol
Ano de publicação:
2019
Tipo de documento:
Article