1,2,4 Triazoles and 1,2,4 Oxadiazoles Scaffold as SGLT2 Inhibitors: Molecular Docking and ADMET Studies

Abstract

Background:Diabetes mellitus (DM) is a metabolic disorder in which blood sugar levels are elevated over a prolonged period of time. SGLT2 inhibitors have recently demonstrated positive effects on diabetes care by minimizing hyperglycemia through decreased glucosuria.Objective:The aim was to carry out molecular docking and ADMET studies of 1,2,4 triazole and 1,2,4 oxadiazole scaffolds as SGLT2 inhibitors.Methods:Structures of newer molecules of two series of 1,2,4 triazoles and 1,2,4 oxadiazoles were drawn by using Chem Draw Ultra 8.0 software. The AutoDock Vina 1.5.6 software was used for the molecular docking studies. In silico ADMET properties were calculated online using admetSAR and pkCSM predictors.Results:We have designed 1563 different 1,2,4 triazoles and 1,2,4 oxadiazoles as SGLT2 inhibitors. A total of 14 compounds from both the triazole and oxadiazole series were shown to have better binding affinity to the SGLT2 protein than canagliflozin. Among them, SSN 10 and SSON 7 showed the highest docking score and binding affinity of -10.7 kcal/mol and -10.5 kcal/mol, respectively. In silico ADMET properties were also calculated in order to determine physiochemical properties, pharmacokinetics and toxicity of best binding molecules. In addition, these molecules were predicted to be non-carcinogens, showing good oral bioavailability and physiochemical characteristics safer with optimal partition coefficient (LogP = 2.07-5.24).Conclusion:Novel SGLT2 inhibitors were designed based on the scaffold of 1,2,4 triazoles and 1,2,4 oxadiazoles resulting in a new lead molecule with a maximum binding affinity; these molecules were also estimated to be noncarcinogenic with low LogP.