In silicodiscovery of potential sodium–glucose cotransporter-2 inhibitors from natural products for treatment of heart failure via molecular docking and molecular dynamics simulation approach

Heart failure (HF) is the end stage of cardiovascular disease. Because of its complex condition and poor prognosis, HF has become an important public health problem in the world. Sodium–glucose cotransporter-2 (SGLT2) is a member of the glucose transporter family. Recently, SGLT2 inhibitors have been applied to treat HF. In this study, the main aim was to discover natural SGLT2 inhibitor from Chinese herbs through docking-based virtual screening. Totally 113 natural compounds of potential SGLT2 inhibitor were identified, which displayed docking affinity higher than six approved inhibitors (dapagliflozin (IC50 = 4.9 nM), canagliflozin (IC50 = 4.4 nM 6.7), ipragliflozin (IC50 = 7.4 nM), empagliflozin (IC50 = 3.1 nM), tofogliflozin (IC50 = 4 nM) and luseogliflozin (IC50 = 2.3 nM)) through docking-based virtual screening. Then, the top three hits (ZINC70455591, ZINC85594065 and ZINC14588133) and six known inhibitors were selected for molecular dynamics simulation and the binding free energy calculation using molecular mechanics Poisson–Boltzmann surface area to demonstrate the stability and affinity of docked complexes. These results pointed out that the three docked complexes were stabilized and the chosen compounds were tightly adhering to the binding site of SGLT2. Besides, pharmacokinetic properties of the selected compounds showed those natural compounds may be potential drug candidates. This study may be contributed to further in vitro and in vivo validation and the development of novel SGLT2 inhibitor for treating HF.Communicated by Ramaswamy H. Sarma