Natural Compounds as DPP-4 Inhibitors: 3D-Similarity Search, ADME Toxicity, and Molecular Docking Approaches

Type 2 diabetes mellitus is one of the most common diseases of the 21st century, caused by a sedentary lifestyle, poor diet, high blood pressure, family history, and obesity. To date, there are no known complete cures for type 2 diabetes. To identify bioactive natural products (NPs) to manage type 2 diabetes, the NPs from the ZINC15 database (ZINC-NPs DB) were screened using a 3D shape similarity search, molecular docking approaches, and ADMETox approaches. Frequently, in silico studies result in asymmetric structures as “hit” molecules. Therefore, the asymmetrical FDA-approved diabetes drugs linagliptin (8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dione), sitagliptin ((3R)-3-amino-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one), and alogliptin (2-[[6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxopyrimidin-1-yl]methyl]benzonitrile) were used as queries to virtually screen the ZINC-NPs DB and detect novel potential dipeptidyl peptidase-4 (DPP-4) inhibitors. The most promising NPs, characterized by the best sets of similarity and ADMETox features, were used during the molecular docking stage. The results highlight that 11 asymmetrical NPs out of 224,205 NPs are potential DPP-4 candidates from natural sources and deserve consideration for further in vitro/in vivo tests