Virtual Screening Using a Ligand-based Pharmacophore Model from Ashitaba (Angelica keiskei K.) Isolates and Molecular Docking to Obtained New Candidates as α-Glucosidase Inhibitors

Abstract

Diabetes mellitus (DM) is a serious, long-term disease when the pancreas doesn't make enough insulin or when the body can't use the insulin it makes well. Type 2 Diabetes Mellitus (T2DM) is a metabolic disorder characterized by elevated blood glucose levels due to insulin resistance and impaired secretion, primarily due to inefficient intestine glucose absorption through the α-glucosidase enzyme. Long-term synthetic drug use can cause issues in the digestive system, kidneys, and liver. Alternative treatments that use herbal products include the ashitaba (Angelica keiskei Koidzumi) plant, which has been evaluated as an α-glucosidase inhibitor. The purpose of this study was to use molecular docking and virtual screening to identify potential α-glucosidase inhibitors from Ashitaba (Angelica keiskei Koidzumi) isolates using a ligand-based pharmacophore model. The screening methods used were ligand-based virtual screening, docking-based virtual screening, and molecular docking. By using 8 training sets of ashitaba isolates, the best model was obtained with 18 features, including two aromatic ring bonds, nine hydrophobic bonds, three hydrogen bond donors, and four hydrogen bond acceptors. The pharmacophore model and docking-based virtual screening simulations of 270,547 molecules in the ZINC Natural Product database and further investigation using molecular docking yielded (R)-N-(diaminomethylene)-3-hydroxy-3-((S)-6-(4-(hydroxyamino)benzyl)-2-(2-hydroxypropan-2-yl)-4-methoxy-5-oxo-2,3-dihydro-5H-furo[3,2-g]chromen-7-yl)propan-1-aminium (ZINC000085594472), (R)-3-((S)-4-(cyclopentyloxy)-6-(4-(hydroxyamino)benzyl)-2-(2-hydroxypropan-2-yl)-5-oxo-2,3-dihydro-5H-furo[3,2-g]chromen-7-yl)-N-(diaminomethylene)-3-hydroxypropan-1-aminium (ZINC000085594416), and (S,E)-1-(1-(2-hydroxy-5-(7-(4-hydroxy-3-methoxyphenyl)-2-isopropyl-5-oxohept-3-en-1-yl)-3-((iminio(methylamino)methyl)amino)phenoxy)cyclopentyl)-N-methylmethanaminium (ZINC000085597046) as the three top hits with binding energies of-16.09,-15.83, and-15.76 kcal/mol, respectively. In conclusion, the (R)-N-(diaminomethylene)-3-hydroxy-3-((S)-6-(4-(hydroxyamino)benzyl)-2-(2-hydroxypropan-2-yl)-4-methoxy-5-oxo-2,3-dihydro-5H-furo[3,2-g]chromen-7-yl)propan-1-aminium (ZINC000085594472) was a more potential candidate for α-glucosidase inhibitor.