1-Deazapurine-Based Alpha-Glucosidase Inhibitors: A Computational Approach for the Treatment of Type 2 Diabetes Mellitus.

INTRODUCTION: Optimal therapeutic control of Type 2 Diabetes (T2D) depends on designing Alpha-Glucosidase Inhibitors (AGIs) with high potency. This study employs a rigorous computational approach to evaluate 1-deazapurine-derived ligands, examining their interaction modes and pharmacochemical attributes. METHODS: The methodology involves drug-likeness evaluation, molecular docking, and Molecular Dynamics (MD) simulations to elucidate the thermodynamic stability of the complexes. A key feature is the integration of a detailed Structure-Activity Relationship (SAR) analysis, demonstrating high consistency between computational rankings and established biological inhibitory profiles. RESULTS: The screening revealed that heteroaromatic rings and bulky aromatic moieties were critical structural determinants for potency. Among the screen compounds, 6-(2-hydroxybenzoyl)-3- (2-phenylethyl)imidazo[4,5-b]pyridine-5-methyl carboxylate (L14), 5-(furan-2-yl)-3-(4- methoxybenzyl)-2-phenyl-7-(trifluoromethyl)imidazo[4,5-b]pyridine (L11), and 3-[2- phenylethyl]-5-thiophene-2-yl-7-(trifluoromethyl)imidazo[4,5-b]pyridine (L4) stood out for their optimal binding affinities. In particular, L11 emerged as the most significant candidate due to its superior interaction energy and structural stability, directly reflecting observed biological trends. DISCUSSION: These results, supported by favorable ADMET profiles, provide a robust scientific rationale for these ligands as lead compounds for T2D management. While the computational insights are highly consistent with observed trends, further studies will address any potential limitations before progressing. CONCLUSION: This study establishes a solid methodological framework for future in vitro and in vivo experimental validation of 1-deazapurine derivatives as potent therapeutic agents.