In Silico discovery and design of molecular glues as a new strategy for development of non-peptidic, small-molecule agonists of GLP-1 receptor

The glucagon-like peptide-1 receptor (GLP-1R) plays a critical role in regulation of blood glucose and energy homeostasis and is an established target for therapeutic agonists against metabolic disorders such as type 2 diabetes and obesity. Existing medications are orthosteric, large molecular weight peptidic molecules that mimics the function of the physiological hormones, and are limited by poor bioavailability, complex manufacturing and considerable side effects, manifesting an urgent need for small molecule agonists. Here we report the identification of sites at the molecular interface of GLP-1R and the G protein that can be employed for binding of small molecules. We have further identified candidate compounds that are capable of binding to those sites via virtual screening, which serve as scaffolds for further design and optimization. Moreover, molecular hybridization has resulted in a compound with augmented binding affinity via concurrent multi-valent binding to adjacent pockets, whose binding free energy is comparable to that of the drug candidate orforglipron which is currently under phase 3 clinical trial. These small-molecule binders can act as molecular glues that promote the assembly of the receptor and the G-protein and thus can potentially allosterically activate the GLP-1R signaling in the absence of physiological hormone binding. These results demonstrate the feasibility of utilizing molecular glues to modulate and activate GLP-1R signaling, which opens wide avenues to the development of orally available, non-peptidic, small-molecule therapeutic GLP-1R agonists that are superior to current peptide-based medications.