-Amylase Modulation: Discovery of Inhibitors Using a Multi-Pharmacophore Approach for Virtual Screening

Better control of postprandial hyperglycemia can be achieved by delaying the absorption of glucose resulting from carbohydrate digestion. Because -amylase initiates the hydrolysis of polysaccharides, the design of -amylase inhibitors can lead to the development of new treatments for metabolic disorders such as typeII diabetes and obesity. In this study, a rational computer-aided approach was developed to identify novel -amylase inhibitors. Three-dimensional pharmacophores were developed based on the binding mode analysis of six different families of compounds that bind to this enzyme. In a stepwise virtual screening workflow, seven molecules were selected from a library of 1.4 million. Five out of seven biologically tested compounds showed -amylase inhibition, and the two most potent compounds inhibited -amylase with IC50 values of 17 and 27m. The scaffold benzylideneacetohydrazide was shared by four of the discovered inhibitors, emerging as a novel drug-like non-carbohydrate fragment and constituting a promising lead scaffold for -amylase inhibition.