Non-sugar α-amylase inhibitor; virtual screening; drug discovery; obesity
540 Chemie 570 Biowissenschaften; Biologie
The enzyme α-amylase is secreted from salivary and pancreatic glands and hydrolyzes α-D(1,4)-glycosidic linkage in carbohydrates such as starch. Its modulation represents the possibility to control postprandial hyperglycemia and is therefore considered an attractive strategy for the prevention or treatment of obesity or type II diabetes. However, only few drug-like α-amylase inhibitors without carbohydrate moieties exist and only sparse information about their mechanistic properties is available. The aim of this study was to discover novel small non-sugar α-amylase inhibitors and their binding modes using rational in silico methodology and biological experiments. To reach this goal, mechanistic 3D pharmacophore models were carefully developed and applied to several virtual screening experiments. Using this approach, about two million compounds could be computationally screened for potential inhibition of α-amylase resulting in the selection of 33 compounds in different virtual screening rounds, which were all biologically tested.
Our initial virtual screening resulted in the discovery of six inhibitors out of fourteen biologically tested compounds (IC50 range: 86 - 300 µM). A subsequent analogue search using the most active and competitive newly identified inhibitor yielded twelve further compounds, out of which six showed slightly better inhibition up to an IC50 of 50 µM. A final, refined virtual screening led to the identification of four improved binders out of seven tested molecules with an IC50 of up to 17 µM. Overall, 50 % of the computationally suggested and selected virtual hits could be experimentally confirmed. Due to their small size, all identified binders show better ligand efficiency values than previously known inhibitors. Hence, these structures are ideal starting points for the design of novel α-amylase inhibitors. The discovered compounds have never been reported as α-amylase inhibitors before and represent novel scaffolds for this specific class of biological activity.
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