Micro-environmental signature of the interactions between druggable target protein, dipeptidyl peptidase-IV, and anti-diabetic drugs

Objective: Druggability of a target protein depends on the interacting micro-environment between the target protein and drugs. Therefore, a precise knowledge of the interacting micro-environment between the target protein and drugs is requisite for drug discovery process. To understand such micro-environment, we performed in silico interaction analysis between a human target protein, Dipeptidyl Peptidase-IV [DPP-4], and three anti-diabetic drugs [saxagliptin, linagliptin and vildagliptin]

Materials and Methods: During the theoretical and bioinformatics analysis of micro-environmental properties, we performed drug-likeness study, protein active site predictions, docking analysis and residual interactions with the protein-drug interface. Micro-environmental landscape properties were evaluated through various parameters such as binding energy, intermolecular energy, electrostatic energy, van der Waals'+H-bond+desolvo energy [EVHD] and ligand efficiency [LE] using different in silico methods. For this study, we have used several servers and software, such as Molsoft prediction server, CASTp server, AutoDock software and LIGPLOT server

Results: Through micro-environmental study, highest log P value was observed for linagliptin [1.07]. Lowest binding energy was also observed for linagliptin with DPP-4 in the binding plot. We also identified the number of H-bonds and residues involved in the hydrophobic interactions between the DPP-4 and the anti-diabetic drugs. During interaction, two H-bonds and nine residues, two H-bonds and eleven residues as well as four H-bonds and nine residues were found between the saxagliptin, linagliptin as well as vildagliptin cases and DPP-4, respectively

Conclusion: Our in silico data obtained for drug-target interactions and micro-environmental signature demonstrates linagliptin as the most stable interacting drug among the tested anti-diabetic medicines

Glucagon-like peptide-1 derivatves and dipeptidyl peptidase-IV inhibitors. New hope for the treatment of type-2 dibetes

Glucagon-like peptide GLP-1 is an endogenous insulinotropic/glucagonostatic hormone that acts in a self-limiting mechanism. It is a multifunctional hormone that leads to insulin release stimulation, liver glucagon breakdown suppression, upregulation of islet cell proliferation, and neogenesis and retardation of gastric emptying. The short half-life and high renal clearance due to degradation via dipeptidyl peptidase-IV DPP-IV, and active glomerular filtration rate make this hormone ineffectual as an exogenous agent. More stable and long acting GLP-1 analogues and DPP-1 inhibitors have been developed with promising clinical value for the treatment of type-2 diabetes. The GLP-1 derivatives have the advantage of decreasing body weight while the DPP-IV inhibitors can be administered orally up to once daily. The mechanism of action as well as the tolerable side effect is astounding. This review article covers this new generation of anti-diabetics