Introduction and Objective: Tirzepatide (TZP), a dual GIP-R and GLP-1R agonist, has demonstrated outstanding efficacy in glycemic control and weight loss. Structural studies have demonstrated the binding mechanism between tirzepatide and the GLP-1R-wilt type (WT). However, since population studies have demonstrated multiple SNPs on the GLP-1R, the mechanisms of TZP binding to GLP-1R variants have yet to be investigated. This study illustrates the interaction dynamics between TZP and GLP-1R variants and provides insight into the change in binding mechanisms and affinities between TZP and GLP-1R WT and variants.Methods: Common variants of the GLP-1R from gnomAD database were chosen for this study. The GLP-1R variant structures bound to TZP were modeled with AI modeling too AlphaFold 3.0, and the conformational stability and dynamic features of the GLP-1R-TZP complexes were subjected to molecular dynamic (MD) simulations. Moreover, we investigated the binding free energy using molecular mechanics-generalized Born surface area (MM/GBSA) to calculate binding energies.Results: The binding energies of the GLP-1R WT bound to TZP (-168 kcal/mol) demonstrated a more robust binding affinity than GLP-1R-R131Q (-155 kcal/mol), GLP-1R-L260F (-161 kcal/mol), GLP-1R-G168S (-148) and GLP-1R-A316T (-139 kcal/mol).Conclusion: In summary, our research offers structural insights into the GLP-1R TZP interaction, with different variants that could potentially approach T2D and obesity, potentially leading to improved patient outcomes through tailored therapy selection based on individual genetic profiles.
A. Mohammad: None. M.H. Dashti: None. F. Almulla: None. J. Abubaker: None.
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