Discovery of novel α-glucosidase inhibitors based on the virtual screening with the homology-modeled protein structure

• Published in: Bioorganic & medicinal chemistry 2008, Vol.16 (1), p.284-292
• Main Authors: Park, Hwangseo, Hwang, Kyo Yeol, Oh, Kyung Hwan, Kim, Young Hoon, Lee, Jae Yeon, Kim, Keun
• Format: Article
• Language: English
• Subjects: Analytical, structural and metabolic biochemistry; Biological and medical sciences; Computer-Aided Design; Diabetes Mellitus - drug therapy; Diabets; Docking; Drug Design; Enzyme assay; Enzyme Inhibitors - chemistry; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Glucose Metabolism Disorders - drug therapy; Glycoside Hydrolase Inhibitors; Homology modeling; Humans; Hydrolases; Inhibitor; Inhibitory Concentration 50; Ligands; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; Protein Binding; Solvents; Structural Homology, Protein; Structure-Activity Relationship; Virtual screening; α-glucosidase
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.09.036

Discovery of α-glucosidase inhibitors has been actively pursued with the aim to develop therapeutics for the treatment of diabetes and the other carbohydrate mediated diseases. We have been able to identify 13 novel α-glucosidase inhibitors by means of a computer-aided drug design protocol involving homology modeling of the target protein and the virtual screening with docking simulations under consideration of the effects of ligand solvation in the binding free energy function. Because the newly discovered inhibitors are structurally diverse and reveal a significant potency with IC 50 values lower than 50 μM, all of them can be considered for further development by structure–activity relationship studies or de novo design methods. Structural features relevant to the interactions of the newly identified inhibitors with the active site residues of α-glucosidase are discussed in detail.