Structure-based design of cathepsin K inhibitors containing a benzyloxy-substituted benzoyl peptidomimetic.
J Med Chem
; 41(21): 3923-7, 1998 Oct 08.
Article
en En
| MEDLINE
| ID: mdl-9767629
ABSTRACT
Peptidomimetic cathepsin K inhibitors have been designed using binding models which were based on the X-ray crystal structure of an amino acid-based, active site-spanning inhibitor complexed with cathepsin K. These inhibitors, which contain a benzyloxybenzoyl group in place of a Cbz-leucine moiety, maintained good inhibitory potency relative to the amino acid-based inhibitor, and the binding models were found to be very predictive of relative inhibitor potency. The binding mode of one of the inhibitors was confirmed by X-ray crystallography, and the crystallographically determined structure is in close qualitative agreement with the initial binding model. These results strengthen the validity of a strategy involving iterative cycles of structure-based design, inhibitor synthesis and evaluation, and crystallographic structure determination for the discovery of peptidomimetic inhibitors.
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Banco de datos:
MEDLINE
Asunto principal:
Péptidos
/
Benzoatos
/
Diseño de Fármacos
/
Catepsinas
/
Inhibidores de Cisteína Proteinasa
Tipo de estudio:
Prognostic_studies
/
Qualitative_research
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
1998
Tipo del documento:
Article
País de afiliación:
Estados Unidos