Integrated Computational Approach for Designing Novel Pyridone‐Based α‐Glucosidase Inhibitors: Insights From 2D‐QSAR, Molecular Docking, Molecular Dynamics Simulations, and MM‐GBSA Analysis
Bouchra Rossafi, Oussama Abchır, Fatima Zahra Guerguer, Meriem Khedraoui, Mhammed El Kouali, Samir Chtita
Abstract
Abstract Diabetes mellitus is a widespread chronic disease marked by elevated blood glucose levels, leading to serious complications. Inhibiting the α‐glucosidase enzyme is a proven strategy to control postprandial hyperglycemia, but current inhibitors often cause adverse effects. This study aimed to identify novel α‐glucosidase inhibitors among 34 pyridone‐based compounds using a QSAR approach. Molecular descriptors were calculated and reduced through principal component analysis to retain the most relevant ones. A predictive QSAR model was developed using multiple linear regression and validated through both internal and external methods, including the definition of the applicability domain. The model demonstrated satisfactory statistical parameters: R 2 = 0.692, R 2 Adj = 0.649, R 2 test = 0.780, and Q 2 = 0.538, indicating its robustness and predictive reliability. Based on this model, seven novel molecules with high predicted inhibitory potential were designed, all falling within the defined applicability domain. These compounds were further evaluated for their drug‐likeness and ADMET profiles, revealing favorable safety characteristics. Molecular docking revealed binding affinities ranging from −9.2 ( M4 ) to −10.4 kcal/mol ( M3 ), comparable to that of the reference drug acarbose (−9.6 kcal/mol), and indicated stable interactions within the active site of α‐glucosidase. To further validate these findings, molecular dynamics simulations and MM‐GBSA calculations were performed to estimate binding free energies and to confirm the stability of the ligand–protein complexes over time, showing that among these designed molecules, M5 and M6 demonstrated particularly stable interactions within the active site of α‐glucosidase. The findings indicate that pyridone derivatives are promising scaffolds for developing effective and safer antidiabetic agents.