Design of Novel Antidiabetic Agents Using 3D‐QSAR, Molecular Docking, ADMET Analysis, Molecular Dynamics, Ligand Transport, and Retrosynthesis

Abstract α‐Glycosidase enzymes are central to the digestion of carbohydrates, which directly affects diabetes mellitus (DM), especially Type 2 diabetes. Molecular docking, molecular dynamics, ligand transport, 3D‐QSAR modeling, pharmacokinetic properties (ADMET), and retrosynthesis were all combined in this computational analysis to find new ligands derived from Indenoquinoxaline‐phenylacrylohydrazide hybrids as α‐glucosidase inhibitors. PLS and comparative molecular similarity index analysis (CoMSIA) were used to generate the best 3D‐QSAR model, which showed good predictive and correlative abilities (Q 2 = 0.652, R 2 = 0.954, and SEE = 0.130). The designed ligands interacted in the enzyme pocket (5ZCC) with several interactions, depending on molecular docking. In addition, molecular dynamics simulations were then used to verify the stability of these ligands over time in the protein's active site. The CaverDock program was implemented to track the movement of designed ligands from the protein's active site to its surface, and also to calculate the biological efficacy of these compounds. In order to demonstrate the various synthesis pathways of the most active molecule, retrosynthesis was finally employed. The findings indicate that because of its capacity to inhibit the α‐glucosidase enzyme, this compound has emerged as the most promising drug candidate for experimental testing both in vitro and in vivo.