Molecular design and biological activity of BCR-ABL tyrosine kinase inhibitors / 中国医学科学院学报
Acta Academiae Medicinae Sinicae
;
(6): 145-149, 2004.
Artículo
en Chino
| WPRIM
| ID: wpr-231971
ABSTRACT
<p><b>OBJECTIVE</b>To discover BCR-ABL tyrosine kinase inhibitors through structure based virtual screening.</p><p><b>METHODS</b>Docking screening against the distinctive inactive conformation of the catalytic domain of BCR-ABL tyrosine kinase was performed on 3D database. The MTT assay was performed to assess the viability of the tumor cells treated with selected compounds. The amount and kinase activity of BCR-ABL protein were detected in the presence of compounds by Western blot analysis and immunoprecipitation.</p><p><b>RESULTS</b>From the top 1,000 compounds with the best DOCK energy score, 15 compounds were selected for biological assay. Eight out of 15 compounds showed notable inhibitory activity against Ph+ human K562 cells with IC50 values ranging from 10 to 200 micromol/L. In cell-based assays of ABL tyrosine phosphorylation, the ability of two kinds of novel, structurally diverse, lead compounds to inhibit ABL kinase activity was observed. However, no significant differences in the amount of BCR-ABL protein were noted on the ABL immunoblot in the presence of these lead compounds.</p><p><b>CONCLUSIONS</b>Two promising lead compounds were discovered to inhibit BCR-ABL tyrosine kinase activity. Virtual screening technique has been proven to narrow down the size of screening compound libraries to the most prospective drug candidates with high success rates.</p>
Texto completo:
Disponible
Índice:
WPRIM (Pacífico Occidental)
Asunto principal:
Fosforilación
/
Simulación por Computador
/
Proteínas Tirosina Quinasas
/
Modelos Moleculares
/
Química
/
Proteínas de Fusión bcr-abl
/
Células K562
/
Evaluación Preclínica de Medicamentos
/
Inhibidores Enzimáticos
/
Genética
Límite:
Humanos
Idioma:
Chino
Revista:
Acta Academiae Medicinae Sinicae
Año:
2004
Tipo del documento:
Artículo
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