Application of molecular modeling to urokinase inhibitors development.
Biomed Res Int
; 2014: 625176, 2014.
Article
en En
| MEDLINE
| ID: mdl-24967388
ABSTRACT
Urokinase-type plasminogen activator (uPA) plays an important role in the regulation of diverse physiologic and pathologic processes. Experimental research has shown that elevated uPA expression is associated with cancer progression, metastasis, and shortened survival in patients, whereas suppression of proteolytic activity of uPA leads to evident decrease of metastasis. Therefore, uPA has been considered as a promising molecular target for development of anticancer drugs. The present study sets out to develop the new selective uPA inhibitors using computer-aided structural based drug design methods. Investigation involves the following stages computer modeling of the protein active site, development and validation of computer molecular modeling methods:
docking (SOL program), postprocessing (DISCORE program), direct generalized docking (FLM program), and the application of the quantum chemical calculations (MOPAC package), search of uPA inhibitors among molecules from databases of ready-made compounds to find new uPA inhibitors, and design of new chemical structures and their optimization and experimental examination. On the basis of known uPA inhibitors and modeling results, 18 new compounds have been designed, calculated using programs mentioned above, synthesized, and tested in vitro. Eight of them display inhibitory activity and two of them display activity about 10 µM.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Programas Informáticos
/
Proteínas Sanguíneas
/
Activador de Plasminógeno de Tipo Uroquinasa
/
Diseño de Fármacos
/
Simulación del Acoplamiento Molecular
Límite:
Humans
Idioma:
En
Revista:
Biomed Res Int
Año:
2014
Tipo del documento:
Article
País de afiliación:
Rusia