Substituent Effects on Drug-Receptor H-bond Interactions: Correlations Useful for the Design of Kinase Inhibitors.
J Med Chem
; 59(23): 10629-10641, 2016 12 08.
Article
en En
| MEDLINE
| ID: mdl-27933961
Investigation of troponin I-interacting kinase (TNNI3K) as a potential target for the treatment of heart failure has produced a series of substituted N-methyl-3-(pyrimidin-4-ylamino)benzenesulfonamide inhibitors that display excellent potency and selectivity against a broad spectrum of protein kinases. Crystal structures of prototypical members bound to the ATP-binding site of TNNI3K reveal two anchoring hydrogen bond contacts: (1) from the hinge region amide N-H to the pyrimidine nitrogen and (2) from the sulfonamide N-H to the gatekeeper threonine. Evaluation of various para-substituted benzenesulfonamides defined a substituent effect on binding affinity resulting from modulation of the sulfonamide H-bond donor strength. An opposite electronic effect emerged for the hinge NH-pyrimidine H-bond interaction, which is further illuminated in the correlation of calculated H-bond acceptor strength and TNNI3K affinity for a variety of hinge binding heterocycles. These fundamental correlations on drug-receptor H-bond interactions may be generally useful tools for the optimization of potency and selectivity in the design of kinase inhibitors.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Diseño de Fármacos
/
Quinasas Quinasa Quinasa PAM
/
Inhibidores de Proteínas Quinasas
Límite:
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2016
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos