In:
Angewandte Chemie International Edition, Wiley, Vol. 55, No. 49 ( 2016-12-05), p. 15277-15281
Abstract:
The chemokine receptor CXCR3 is a G protein‐coupled receptor that conveys extracellular signals into cells by changing its conformation upon ligand binding. We previously hypothesized that small‐molecule allosteric CXCR3‐agonists do not bind to the same allosteric binding pocket as 8‐azaquinazolinone‐based negative allosteric modulators. We have now performed molecular‐dynamics (MD) simulations with metadynamics enhanced sampling on the CXCR3 system to refine structures and binding modes and to predict the CXCR3‐binding affinities of the biased allosteric agonist FAUC1036 and the negative allosteric modulator RAMX3. We have identified two distinct binding sites; a “shallow” and a second “deeper” pocket to which the biased allosteric agonist FAUC1036 and negative allosteric modulator RAMX3 bind, respectively.
Type of Medium:
Online Resource
ISSN:
1433-7851
,
1521-3773
DOI:
10.1002/anie.201607831
Language:
English
Publisher:
Wiley
Publication Date:
2016
detail.hit.zdb_id:
2011836-3
detail.hit.zdb_id:
123227-7
