Pharmacophore-Based 3D-QSAR and Molecular Docking Studies of Novel 1,3,4-Thiadiazole Derivatives as Potential α-Glucosidase Inhibitors

Abstract

Background: Metabolic Disorder Type 2 Diabetes mellitus (T2DM) is a chronic disease that involves hyperglycemia due to insulin resistance and impaired insulin secretion. α-glucosidase inhibition has been proven to be a therapeutic approach for controlling postprandial hyperglycemia and is a well-established treatment for T2DM. 1,3,4-thiadiazole is a promising pharmacophore among heterocyclic scaffolds due to its broad range of biological activities, including α-glucosidase inhibition. Purpose: The present study was designed to identify and optimize novel 1,3,4-thiadiazole derivatives as α-glucosidase inhibitors using an integrated computer-aided drug design (CADD) approach that includes pharmacophore modeling, 3D-QSAR, molecular docking, optimization of R-groups, and ADMET prediction. Methods: A total of 34 reported 1,3,4-thiadiazole derivatives were analyzed to build an optimal pharmacophore model (AADHR₃) as well as atom-based (R² = 0.799, Q² = 0.822) and Gaussian field-based 3D-QSAR models (R² = 0.967, Q² = 0.682). The structurally optimized lead compounds were then identified by molecular docking, R-group optimization, and ADMET prediction. Results: The analysis of the contour map showed that bulky hydrophobic groups in the R₁ position and electron-withdrawing groups in the R₂ position were beneficial for enhancing α-glucosidase inhibitory activity. The docking score of five compounds was comparable or better than that of acarbose (−6.260 kcal/mol), with the best score being compound 25 (−6.686 kcal/mol). The designed derivatives (DM1 (−7.625 kcal/mol), DM2 (−7.418 kcal/mol), and DM3 (−7.284 kcal/mol)) showed better binding abilities and favorable interactions with Arg281, Asp282, Asp404, Asp518, Asp616, His674, and Phe525, in addition to promising ADMET properties. Conclusion: Pharmacophore analysis, 3D-QSAR, molecular docking, SAR, and ADMET studies indicated that the 1,3,4-thiadiazole scaffold could be a promising template for designing potent α-glucosidase inhibitors. The optimized derivatives, especially DM1–DM3, are good lead candidates for further development into therapeutic drugs for T2DM.