Discovery of potent and selective urea-based ROCK inhibitors: Exploring the inhibitor's potency and ROCK2/PKA selectivity by 3D-QSAR, molecular docking and molecular dynamics simulations.
Bioorg Med Chem
; 23(10): 2505-17, 2015 May 15.
Article
em En
| MEDLINE
| ID: mdl-25882521
ABSTRACT
An activity model and a selectivity model from 3D-QSAR studies were established by CoMFA and CoMSIA to explore the SAR. Then docking was used to study the binding modes between ligand and kinases (ROCK2 and PKA), and the molecular docking results were further validated by MD simulations. Computational results suggested that substitution containing positive charge attached to the middle phenyl ring, or electropositive group in urea linker was favored for both activity and ROCK2/PKA selectivity. Finally, three compounds were designed, and biological evaluation demonstrated that these molecular models were effective for guiding the design of potent and selective ROCK inhibitors.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ureia
/
Proteínas Recombinantes
/
Proteínas Quinases Dependentes de AMP Cíclico
/
Inibidores de Proteínas Quinases
/
Quinases Associadas a rho
/
Bibliotecas de Moléculas Pequenas
Limite:
Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article