Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Discovered through X-ray Fragment Screening.
J Med Chem
; 59(11): 5356-67, 2016 06 09.
Article
em En
| MEDLINE
| ID: mdl-27167608
ABSTRACT
Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirazóis
/
Tiazóis
/
1-Alquil-2-acetilglicerofosfocolina Esterase
/
Inibidores Enzimáticos
/
Descoberta de Drogas
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
/
Risk_factors_studies
/
Screening_studies
Limite:
Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Reino Unido