Dual inhibitors of Janus kinase 2 and 3 (JAK2/3): designing by pharmacophore- and docking-based virtual screening approach.
Mol Divers
; 18(2): 253-67, 2014 May.
Article
em En
| MEDLINE
| ID: mdl-24415188
ABSTRACT
JAK2 and JAK3 are non-receptor protein tyrosine kinases implicated in B-cell- and T-cell-mediated diseases. Both enzymes work via different pathways but are involved in the pathogenesis of common lymphoid-derived diseases. Hence, targeting both Janus kinases together can be a potential strategy for the treatment of these diseases. In the present study, two separate pharmacophore-based 3D-QSAR models ADRR.92 (Q(2)(test)0.663, R(2)(train) 0.849, F value 219.3) for JAK2 and ADDRR.142 (Q(2)(test)0.655, R(2)(train) 0.869, F value 206.9) for JAK3 were developed. These models were employed for the screening of a PHASE database of approximately 1.5 million compounds; subsequently, the retrieved hits were screened employing docking simulations with JAK2 and JAK3 proteins. Finally, ADME properties of screened dual inhibitors displaying essential interactions with both proteins were calculated to filter candidates with poor pharmacokinetic profiles. These candidates could serve as novel therapeutic agents in the treatment of lymphoid-related diseases.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Inibidores de Proteínas Quinases
/
Janus Quinase 2
/
Janus Quinase 3
/
Simulação de Acoplamento Molecular
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article