Structure-based design of the first potent and selective inhibitor of human non-pancreatic secretory phospholipase A2.
Nat Struct Biol
; 2(6): 458-65, 1995 Jun.
Article
en En
| MEDLINE
| ID: mdl-7664108
ABSTRACT
A lead compound obtained from a high volume human non-pancreatic secretory phospholipase A2 (hnps-PLA2) screen has been developed into a potent inhibitor using detailed structural knowledge of inhibitor binding to the enzyme active site. Four crystal structures of hnps-PLA2 complexed with a series of increasingly potent indole inhibitors were determined and used as the structural basis for both understanding this binding and providing valuable insights for further development. The application of structure-based drug design has made possible improvements in the binding of this screening lead to the enzyme by nearly three orders of magnitude. Furthermore, the optimized structure (LY311727) displayed 1,500-fold selectivity when assayed against porcine pancreatic s-PLA2.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fosfolipasas A
/
Diseño de Fármacos
/
Indoles
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Nat Struct Biol
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
1995
Tipo del documento:
Article
País de afiliación:
Estados Unidos