Structural Analysis of a New Saccharomyces cerevisiae α-glucosidase Homology Model and Identification of Potential Inhibitor Enzyme Docking Sites

Abstract

Publication date: October 2020 (Robinson et al., 1991). There have been countless studies on inhibition of the active site in α-glucosidase using sugar mimics, which lead to the creation of Acarbose and Miglitol medications (Clissold and Edwards, 1988; Laube, 2002; Scott and Spencer, 2000; Sels et. al., 1999). However, these drugs induce side effects, including gastrointestinal pain, and constipation/diarrhea (Aoki et. al., 2010). The use of sugar mimicking drugs brings about the complication of interaction with other naturally occurring sugar-binding enzymes, which can lead to gastrointestinal distress. The identification of natural allosteric inhibitors, which do not mimic sugars and bind to an area on the enzyme distinct from the active site, may reveal more potent inhibitors with fewer adverse effects; the inhibition studies of α-glucosidase in vitro and in vivo have created a pool of known and potential inhibitors with a specific flavonoid scaffold (Kim et. al., 2000; Singh et. al., 2014; Tadera et. al., 2006; Xu, 2010). Flavonoids consist of two specific chemical moieties: a benzopyran containing the A and C-rings, and a phenyl group referred to as the B-ring (Figure 1) (Panche et. al., 2016). Several flavonoids have previously been studied for inhibitory effects on α-glucosidase (Proença et al., 2017). Our goal is to identify and confirm how and where these compounds are binding to α-glucosidase as well as to verify their inhibitory mechanism because this will broaden the understanding of how allosteric inhibition of α-glucosidase works at the molecular level and inform future drug design. After investigating published research and compiling a list of natural inhibitors with IC50 values similar to acarbose, we decided on a series of flavonoids was identified for docking INTRODUCTION α-glucosidase (EC 3.2.1.20) is a digestive enzyme which aids in the hydrolysis of α(1-4)-linked α-D-glucose molecules at the terminal end of polysaccharides (Jeske et. al., 2018). Inhibiting this protein slows the release of free glucose in the small intestines. The therapeutic advantage of inhibiting α-glucosidase is that it can be used to treat certain diseases associated with abnormally high blood glucose concentrations, such as Type II diabetes (diabetes mellitus). Those with diabetes mellitus do not secrete enough insulin following a meal, resulting in post-prandial hyperglycemia (Alberti and Zimmet, 1998). Inhibiting α-glucosidase can stop the body from entering a state of hyperglycemia by slowing the initial absorption of glucose in the blood stream, giving insulin a more manageable increase in blood-glucose levels Structural Analysis of a New Saccharomyces cerevisiae α-glucosidase Homology Model and Identification of Potential Inhibitor Enzyme Docking Sites