Danuglipron and orforglipron engage GLP-1R through materially different interfaces: an unbiased molecular dynamics study
GLP-1R is among the most heavily pursued targets in metabolic disease, but its natural agonist is a 30-residue peptide that must be injected. Two oral non-peptide agonists have reached late-stage trials. Cryo-EM studies have already shown that danuglipron and CHU-128, a close analogue of orforglipron, occupy the receptor differently, but not how either interface behaves over time. We ran 500 ns…
Danuglipron and orforglipron, two oral non-peptide agonists reaching late-stage trials for GLP-1R as a metabolic disease target, have distinct interfaces with the receptor according to a molecular dynamics study. Unbiased all-atom simulations of GLP-1R bound to GLP-1, danuglipron (PF-06882961), and orforglipron (LY3502970) were conducted in a POPC bilayer without the G protein.
While CHU-128, a close analogue of orforglipron, had been simulated previously, this is the first simulation of orforglipron. The study found that orforglipron utilizes ring systems mainly in one receptor domain, with 99.7% of its contacts in the extracellular domain, whereas danuglipron engages receptors in both domains. Danuglipron had lower contact occupancy compared to orforglipron, with only 33% of its contacts exceeding 90% occupancy at 100 ns, making it the outlier on certain measures.
The distinct structural occupations of these two drugs in the GLP-1R receptor indicate different ways of interacting with the target.
Written by urgent.news from bioRxiv's reporting — not their text. Machine-written — may contain errors; check the original before relying on it.
