Structure-based design of cathepsin K inhibitors containing a benzyloxy-substituted benzoyl peptidomimetic.
J Med Chem
; 41(21): 3923-7, 1998 Oct 08.
Article
em 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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Base de dados:
MEDLINE
Assunto principal:
Peptídeos
/
Benzoatos
/
Desenho de Fármacos
/
Catepsinas
/
Inibidores de Cisteína Proteinase
Tipo de estudo:
Prognostic_studies
/
Qualitative_research
Idioma:
En
Ano de publicação:
1998
Tipo de documento:
Article