The molecular mechanism studies of chirality effect of PHA-739358 on Aurora kinase A by molecular dynamics simulation and free energy calculations.
J Comput Aided Mol Des
; 25(2): 171-80, 2011 Feb.
Article
en En
| MEDLINE
| ID: mdl-21222017
Aurora kinase family is one of the emerging targets in oncology drug discovery and several small molecules targeting aurora kinases have been discovered and evaluated under early phase I/II trials. Among them, PHA-739358 (compound 1r) is a 3-aminopyrazole derivative with strong activity against Aurora A under early phase II trial. Inhibitory potency of compound 1r (the benzylic substituent at the pro-R position) is 30 times over that of compound 1s (the benzylic substituent at the pro-S position). In present study, the mechanism of how different configurations influence the binding affinity was investigated using molecular dynamics (MD) simulations, free energy calculations and free energy decomposition analysis. The predicted binding free energies of these two complexes are consistent with the experimental data. The analysis of the individual energy terms indicates that although the van der Waals contribution is important for distinguishing the binding affinities of these two inhibitors, the electrostatic contribution plays a more crucial role in that. Moreover, it is observed that different configurations of the benzylic substituent could form different binding patterns with protein, thus leading to variant inhibitory potency of compounds 1r and 1s. The combination of different molecular modeling techniques is an efficient way to interpret the chirality effects of inhibitors and our work gives valuable information for the chiral drug design in the near future.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Pirazoles
/
Benzamidas
/
Proteínas Serina-Treonina Quinasas
/
Inhibidores de Proteínas Quinasas
/
Simulación de Dinámica Molecular
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
J Comput Aided Mol Des
Asunto de la revista:
BIOLOGIA MOLECULAR
/
ENGENHARIA BIOMEDICA
Año:
2011
Tipo del documento:
Article
Pais de publicación:
Países Bajos