Binding interaction of SGLT with sugar and thiosugar by the molecular dynamics simulation.
The human sodium-glucose co-transporter 2 (hSGLT2) is a transporter responsible for reabsorption of glucose in the proximal convoluted tubule of the kidney. hSGLT2 inhibitors, including luseogliflozin, have been developed as drugs for type 2 diabetes mellitus. Only luseogliflozin contains a thiosugar ring in its chemical structure, while other hSGLT2 inhibitors contain glucose rings. Consequently, we focused on the binding interactions of hSGLT2 with sugars and thiosugars. We first revealed that the binding affinities of thiosugars are stronger than those of sugars through molecular dynamics simulations of Vibrio parahaemolyticus, sodium-galactose co-transporter, and human hSGLT2. We then demonstrated that Na(+) dissociates from the protein to the cytoplasmic solution more slowly in the thiosugar system than in the sugar system. These differences between sugars and thiosugars are discussed on the basis of the different binding modes due to the atom at the 5-position of the sugar and thiosugar rings. Finally, as a result of Na(+) dissociation, we suggest that the dissociation of thiosugars is slower than that of sugars.
['Tamura|Yunoshin|Y|', 'Miyagawa|Hiroh|H|', 'Yoshida|Tatsusada|T|', 'Chuman|Hiroshi|H|']
D001426:Bacterial Proteins D001665:Binding Sites D001667:Binding, Competitive D005690:Galactose D005947:Glucose D006801:Humans D007700:Kinetics D056004:Molecular Dynamics Simulation D015394:Molecular Structure D025341:Principal Component Analysis D011485:Protein Binding D017433:Protein Structure, Secondary D017434:Protein Structure, Tertiary D012964:Sodium D051247:Sodium-Glucose Transport Proteins D051297:Sodium-Glucose Transporter 2 D013816:Thermodynamics D054330:Thiosugars D014736:Vibrio parahaemolyticus
Molecular dynamics Co-transporter Luseogliflozin Bennett's acceptance ratio method Binding free energy