In silico approach to identify novel dipeptidyl peptidase-4 (DPP4) and alpha-glucosidase inhibitors for type-2 diabetes
Type 2 diabetes mellitus (T2D) is one of the leading causes of renal failure, blindness, and death worldwide. Although various proteins are involved in T2D, the alpha-glucosidase and the DPP4 are the potential drug targets as if inhibit these proteins, the alpha-glucosidase cannot break down the complex sugar molecule into smaller one, DPP4 will not cleave the incretin peptides such as gastric inhibitory polypeptide (GIP) and glucagon-like peptide (GLP-1) are responsible for the modulation of postprandial blood glucose by promoting insulin secretion. In the current study, we tried to find some common inhibitors for intestinal alpha-glucosidase (N and C terminal) and lysosomal alpha-glucosidase, so that di and oligosaccharides will not broken-down into glucose in the intestine and glucose absorption will be reduced from the intestine. As we inhibit lysosomal alpha-glucosidase, the conversion of glycogen to glucose in liver and muscle will be hindered. To achieve this combined action, we performed the virtual screening of molecules from PubChem, chEMBL and DrugBank. We found that the CHEMBL3349443, CHEMBL1603891, CHEMBL2079351, CHEMBL1363818 and CHEMBL367666 are the best molecules to compare with approved drugs Voglibose and Miglitol. Except CHEMBL367666 all other molecules are heterocyclic. From the DrugBank dataset Neamine (DB04808), Gentamicin (DB00798), Netilmicin (DB00955), Sisomicin (DB12604) and Amikacin (DB00479 were finalized as the common molecule which inhibit all three protein targets. All of them are heterocyclic antibiotics, and three of them are approved drug and another two are experimental and investigational drugs. The chEMBL molecules CHEMBL373665, CHEMBL98860, CHEMBL366549, CHEMBL184624 and CHEMBL214580 have better binding affinity with DPP4 than the known approved drugs. All of them are heterocyclic molecules. The current work sheds light on diabetic research and the finalized molecules can be explore further.