Cheminformatics-Based Screening for Α-Amylase and Α-Glucosidase Inhibitors from Natural Products Activity and Species Source Database for Management of Postprandial Hyperglycemia

Abstract

Postprandial hyperglycemia, typical manifestation of Type 2 Diabetes Mellitus (T2DM), is associated with notable global mortality over the past years. One way of preventing this condition’s advancement is by delaying glucose absorption rate through inhibition of α-amylase and α-glucosidase enzymatic activities. Conventional methods of drug discovery have led to isolation of molecules with a variety of biological activities against diverse illnesses. For instance, the Natural Products Activity and Species database (NPASS) comprise of 30,926 unique active natural compounds from 25,041 sources, primarily from organisms. Most of these compounds are used in Traditional Chinese Medicine (TCM) and other traditional medicine, but there is no detailed information regarding their use to control T2DM. Additionally, current antidiabetic drugs such as Acarbose, Miglitol, Voglibose and 1-deoxynojirimicin (DNJ) have been associated with unpleasant side effects, hence necessitating the need for finding a more efficacious and safer antidiabetic drug. Therefore, the current study utilized computer aided drug design (CADD), as a quick and affordable method to find a substitute drug template from NPASS database that can be used to control postprandial hyperglycemia by modulating the activity of α-amylase and α-glucosidase enzymes. The Natural Products Activity and Species source database (30,926 compounds) was screened in silico, with a focus on evaluating drug-likeness, toxicity profiles and ability to bind on a target protein. Two molecules NPC204580 (Chrotacumine C) and NPC137813 (1-O- (2-Methoxy-4-Acetylphenyl)-6-O-(E-Cinnamoyl)- β -D-Glucopyranoside) were identified as potential dual inhibitors for α-amylase and α-glucosidase. Their docking scores was -14.46 kcal/mol and -12.58 kcal/mol for α-amylase, and -8.42 kcal/mol and -8.76 kcal/mol for α-glucosidase, respectively. Moreover, 100 nanoseconds (ns) molecular dynamic simulations revealed that the two molecules were stable on the receptor’s active sites based on analysis metrics such as root mean square deviation (RMSD), root mean square fluctuations (RMSF) and free binding energy calculation as per the Generalized Born surface area (MM/GBSA). Additionally, the molecules demonstrated acceptable pharmacokinetic and toxicological profiles as substances that can be easily delivered to the intended site of action. Therefore, the two compounds are thus promising therapeutic agents for T2DM that merit further investigation (in-vitro and in-vivo) due to their excellent binding energies, encouraging pharmacokinetics and toxicity profiles, as well as the stability demonstrated in simulation studies.