Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual Screening.
Biomolecules
; 11(7)2021 06 23.
Article
in En
| MEDLINE
| ID: mdl-34201418
ABSTRACT
Allosteric modulators have emerged with many potential pharmacological advantages as they do not compete the binding of agonist or antagonist to the orthosteric sites but ultimately affect downstream signaling. To identify allosteric modulators targeting an extra-helical binding site of the glucagon-like peptide-1 receptor (GLP-1R) within the membrane environment, the following two computational approaches were applied structure-based virtual screening with consideration of lipid contacts and ligand-based virtual screening with the maintenance of specific allosteric pocket residue interactions. Verified by radiolabeled ligand binding and cAMP accumulation experiments, two negative allosteric modulators and seven positive allosteric modulators were discovered using structure-based and ligand-based virtual screening methods, respectively. The computational approach presented here could possibly be used to discover allosteric modulators of other G protein-coupled receptors.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Drug Delivery Systems
/
Drug Discovery
/
Glucagon-Like Peptide-1 Receptor
Type of study:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Biomolecules
Year:
2021
Document type:
Article
Affiliation country: