IMPACT OF TYPE 2 DIABETES-ASSOCIATED DIPEPTIDYL PEPTIDASE-4 (DPP-4) MUTATIONS ON LIGAND BINDING AND ENZYME ACTIVITY MODULATED BY NATURAL COMPOUNDS

Authors : Gizem Köprülülü Küçük

Pages : 169-178

Doi:10.22531/muglajsci.1783212

View : 61 | Download : 166

Publication Date : 2025-12-31

Article Type : Research Paper

Abstract :Type 2 diabetes is a chronic metabolic disorder marked by insulin resistance and β-cell dysfunction. DPP-4 inhibitors help regulate glucose by prolonging the effects of GLP-1 and GIP. This study examined how three mutations in the DPP-4 enzyme, V266I, G189E, and S437T, affect binding affinity with natural ligands (caffeic acid, proanthocyanidin, and palmatine) using in silico methods. The amino acid sequence of DPP-4 was obtained from UniProt, and mutation effects were assessed via HOPE. 3D models were generated through Swiss-Model and validated with SAVES v6.1, showing high structural accuracy (e.g., ERRAT: 97.3%). Molecular docking with AutoDock Vina showed strong binding of palmatine and Caffeic Acid Phenethyl Ester (CAPE) to wild-type DPP-4 (–7.6 kcal/mol). However, all three mutations led to reduced binding affinity, with scores ranging from –5.3 to –6.9 kcal/mol. The G189E mutation, in particular, caused a notable drop in binding energy due to the disruption of electrostatic and hydrophobic interactions. These structural changes suggest that such mutations may decrease the efficacy of DPP-4 inhibitors. Therefore, they represent critical factors to consider in drug design targeting this enzyme.
Keywords : Tip 2 diyabet, DPP-4, Nokta mutasyonu, Moleküler yerleştirme, Doğal bileşikler

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