title: Binding interaction of SGLT with sugar and thiosugar by the molecular dynamics simulation.
abstract: 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.
authors.affiliation: Chemistry Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan.
authors.forename: Yunoshin
authors.initials: Y
authors.lastname: Tamura
authors.affiliation: Chemistry Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan.
authors.forename: Hiroh
authors.initials: H
authors.lastname: Miyagawa
authors.affiliation: Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78 Shomachi, Tokushima 770-8505, Japan.
authors.forename: Tatsusada
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78 Shomachi, Tokushima 770-8505, Japan. Electronic address: hchuman@tokushima-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Chuman
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D005690:Galactose / Q000737:chemistry* / Q000378:metabolism; D005947:Glucose / Q000737:chemistry* / Q000378:metabolism; 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 / Q000737:chemistry; D051247:Sodium-Glucose Transport Proteins / Q000737:chemistry / Q000378:metabolism; D051297:Sodium-Glucose Transporter 2 / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics; D054330:Thiosugars / Q000737:chemistry* / Q000378:metabolism; D014736:Vibrio parahaemolyticus / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; C089180:SLC5A2 protein, human; D051247:Sodium-Glucose Transport Proteins; D051297:Sodium-Glucose Transporter 2; D054330:Thiosugars; D012964:Sodium; D005947:Glucose; D005690:Galactose
keywords: Bennett's acceptance ratio method; Binding free energy; Co-transporter; Luseogliflozin; Molecular dynamics