X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists.
Angew Chem Int Ed Engl
; 59(38): 16536-16543, 2020 09 14.
Article
en En
| MEDLINE
| ID: mdl-32542862
ABSTRACT
We present a robust protocol based on iterations of free energy perturbation (FEP) calculations, chemical synthesis, biophysical mapping and X-ray crystallography to reveal the binding mode of an antagonist series to the A2A adenosine receptor (AR). Eight A2A AR binding site mutations from biophysical mapping experiments were initially analyzed with sidechain FEP simulations, performed on alternate binding modes. The results distinctively supported one binding mode, which was subsequently used to design new chromone derivatives. Their affinities for the A2A AR were experimentally determined and investigated through a cycle of ligand-FEP calculations, validating the binding orientation of the different chemical substituents proposed. Subsequent X-ray crystallography of the A2A AR with a low and a high affinity chromone derivative confirmed the predicted binding orientation. The new molecules and structures here reported were driven by free energy calculations, and provide new insights on antagonist binding to the A2A AR, an emerging target in immuno-oncology.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Termodinámica
/
Receptor de Adenosina A2A
/
Antagonistas de Receptores Purinérgicos P1
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Año:
2020
Tipo del documento:
Article
País de afiliación:
Suecia