Simulated annealing molecular dynamics and ligand-receptor contacts analysis for pharmacophore modeling.
Future Med Chem
; 9(11): 1141-1159, 2017 07.
Article
en En
| MEDLINE
| ID: mdl-28722471
ABSTRACT
AIM:
Ligand-based pharmacophore modeling requires long list of inhibitors, while pharmacophores based on single ligand-receptor crystallographic structure can be too restricted or promiscuous.METHODOLOGY:
This prompted us to combine simulated annealing molecular dynamics (SAMD) with ligand-receptor contacts analysis as means to construct pharmacophore model(s) from single ligand-receptor complex. Ligand-receptor contacts that survive numerous heating-cooling SAMD cycles are considered critical and are used to guide pharmacophore development.RESULTS:
This methodology was implemented to develop pharmacophores for acetylcholinesterase and protein kinase C-θ. The resulting models were validated by receiver-operating characteristic analysis and in vitro bioassay. Assay identified four new protein kinase C-θ inhibitors among captured hits, two of which exhibited nanomolar potencies.CONCLUSION:
The results illustrate the ability of the new method to extract valid pharmacophores from single ligand-protein complex.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Acetilcolinesterasa
/
Inhibidores de la Colinesterasa
/
Simulación de Dinámica Molecular
/
Proteína Quinasa C-theta
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Future Med Chem
Año:
2017
Tipo del documento:
Article
País de afiliación:
Jordania