The Glucagon-like peptide 1 receptor (GLP-1R) is a well-established target for the treatment of type 2 diabetes and GLP-1R agonist-based therapies represent an effective approach which results in several GLP-1 analog drugs. However, the development of nonpeptidic agonist drugs targeting GLP-1R remains unsuccessful. A promising strategy aims to develop orally bioavailable, small-molecule positive allosteric modulators of GLP1-1R. Taking advantage of the recently reported cryo-EM structure of GLP-1R at its active state, we have performed structure-based screening studies which include potential allosteric binding site prediction and in silico screening of drug-like compounds, and conducted in vitro testing and site-specific mutagenesis studies. One compound with low molecular weight was confirmed as a positive allosteric modulator of GLP-1R as it enhances GLP-1's affinity and efficacy to human GLP-1R in a dose dependent manner. This compound also stimulates insulin secretion synergistically with GLP-1. With the molecular weight of 399, this compound represents one of the smallest known GLP-1R PAMs, and demonstrates other favorable drug-like properties. Site-specific mutagenesis studies confirmed that the binding site of this compound partially overlaps with that of a known antagonist in the transmembrane domain. These results demonstrate that structure-based approach is useful for discovering nonpeptidic allosteric modulators of GLP-1R and the compound reported here is valuable for further drug development.
Keywords: Glucagon-like peptide 1 receptor; Positive allosteric modulator; Type-2 diabetes; Virtual screening.