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

Discovery of alpha-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 alpha-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 microM, 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 alpha-glucosidase are discussed in detail.