IN SILICO INVESTIGATION OF THE EFFECTS OF GLP-1R VARIANTS ON EXENDIN4 BINDING PROPERTIES
ARCENG 6. INTERNATIONAL ANKARA SCIENTIFIC STUDIES CONGRESS , Ankara, Türkiye, 3 - 05 Temmuz 2026, ss.211-221, (Tam Metin Bildiri)
- Yayın Türü: Bildiri / Tam Metin Bildiri
- Basıldığı Şehir: Ankara
- Basıldığı Ülke: Türkiye
- Sayfa Sayıları: ss.211-221
- Açık Arşiv Koleksiyonu: AVESİS Açık Erişim Koleksiyonu
- Yıldız Teknik Üniversitesi Adresli: Evet
Özet
The glucagon-like peptide-1 receptor (GLP-1R) is a receptor that regulates glucose-dependent insulin secretion and represents a critical pharmacological target in the treatment of type 2 diabetes mellitus (T2DM) and obesity. Due to the short half-life of the endogenous GLP-1 hormone, more potent receptor agonists, such as Exendin-4, which exhibit resistance to the dipeptidyl peptidase-4 (DPP-4) enzyme, have been introduced into clinical use. However, in clinical practice, interindividual variability has been observed in patients' responses to GLP-1R agonists, particularly with respect to the extent of weight loss and the frequency of adverse effects. One of the underlying causes of this variability is that single nucleotide polymorphisms (SNPs) in the GLP-1R gene can alter the three-dimensional structure of the receptor and its ligand-binding affinity. In this study, the structural and thermodynamic effects of GLP-1R variants on Exendin-4 binding properties were comprehensively analyzed using in silico mutagenesis and structural bioinformatics tools. As the first step of the study, all possible base substitutions within the GLP-1R gene were examined using the Nucleotide Transformer (NT) and prioritized according to their ΔLL scores. Following this screening, the ten highest-risk candidate variants were analyzed in terms of pathogenicity predictions and thermodynamic stability changes. Furthermore, molecular docking analyses of the modeled variants generated using PyMOL with Exendin-4, performed using the HADDOCK platform, revealed the potential effects of these variants on thermodynamic stability and ligand affinity. Accordingly, the W284C and I147V variants were predicted to weaken the binding interactions with Exendin-4 relative to the wild-type receptor, whereas the G446E and A158D variants were predicted to exhibit a stronger interaction potential. The findings provide a structural basis for personalized incretin therapies by elucidating the mechanisms underlying pharmacogenomic resistance and hypersensitivity at the structural level.