Strengthening Semaglutide-GLP-1R Binding Affinity via a Val27-Arg28 Exchange in the Peptide Backbone of Semaglutide: A Computational Structural Approach

Semaglutide is a glucagon-like peptide 1 analog used for the treatment of patients with type 2 diabetes mellitus. With 94% sequence similarity to human GLP-1, semaglutide is a glucagon-like peptide-1 receptor (GLP-1R) agonist, which binds directly to GLP-1R, causing various beneficial downstream effects that reduce blood glucose. Incorporating currently (June 21, 2021) available experimental structural data in PDB of semaglutide and GLP-1R, and with a set of computational structural and biophysical analysis, this short paper for the first time puts forward an experimentally testable hypothesis: semaglutide is able to bind tighter to GLP-1R via a simple Val27-Arg28 exchange in its peptide backbone.