Ligands for the GLP-1 Receptor and Methods for Discovery Thereof

Abstract

Disclosed is the three-dimensional (3-D) structure of the GLP-1 receptor (GLP-1R) and methods by which the structure may be used to develop compounds that bind to, and/or modulate the GLP-1R. The technology described herein may be applied to the development of compounds that target the GLP-1R, or may be used to develop target compound that may bind to, and/or modulate the activity of the GLP-1R.

What is claimed is: 
     
         1 . A method for agonizing the human GLP-1 receptor (GLP-1R), the method comprising the steps of:
 contacting a cell expressing GLP-1R with a compound,
 wherein the compound has a molecular weight of less than 2000 daltons, 
 wherein the compound does not interfere with the binding of native GLP-1 to the GLP-1R; 
 wherein there is at least one atomic interaction between the compound and at least one of the amino acid residues selected from the group consisting of Ser31, Thr35, Trp39, Arg43, Thr65, Phe66, Glu68, Asp67, Tyr69, Trp91, Leu89, Tyr88, Arg121, Arg102, Leu123, Glu127, Trp110 and Glu128 of the GLP-1R; and 
 wherein the atomic interaction between the compound and the GLP-1R comprises at least one atomic interaction between the potential modulator compound and at least one of the amino acid residues selected from the group consisting of Arg376 and Arg380 of the GLP-1R.