title: Developing hypothetical inhibition mechanism of novel urea transporter B inhibitor.
abstract: Urea transporter B (UT-B) is a membrane channel protein that specifically transports urea. UT-B null mouse exhibited urea selective urine concentrating ability deficiency, which suggests the potential clinical applications of the UT-B inhibitors as novel diuretics. Primary high-throughput virtual screening (HTVS) of 50000 small-molecular drug-like compounds identified 2319 hit compounds. These 2319 compounds were screened by high-throughput screening using an erythrocyte osmotic lysis assay. Based on the pharmacological data, putative UT-B binding sites were identified by structure-based drug design and validated by ligand-based and QSAR model. Additionally, UT-B structural and functional characteristics under inhibitors treated and untreated conditions were simulated by molecular dynamics (MD). As the result, we identified four classes of compounds with UT-B inhibitory activity and predicted a human UT-B model, based on which computative binding sites were identified and validated. A novel potential mechanism of UT-B inhibitory activity was discovered by comparing UT-B from different species. Results suggest residue PHE198 in rat and mouse UT-B might block the inhibitor migration pathway. Inhibitory mechanisms of UT-B inhibitors and the functions of key residues in UT-B were proposed. The binding site analysis provides a structural basis for lead identification and optimization of UT-B inhibitors.
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: School of Medicine, College of Medicine, China Medical University, Taichung, 40402, Taiwan.
authors.forename: Weng Ieong
authors.initials: WI
authors.lastname: Tou
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.|School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, 442000, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
authors.forename: Huiwen
authors.initials: H
authors.lastname: Ren
authors.affiliation: School of Medicine, College of Medicine, China Medical University, Taichung, 40402, Taiwan.|Human Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.|Department of Biomedical Informatics, Asia University, Taichung, 41354, Taiwan.|Research Center for Chinese Medicine &Acupuncture, China Medical University, Taichung 40402, Taiwan.
authors.forename: Calvin Yu-Chian
authors.initials: CY
authors.lastname: Chen
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
authors.forename: Baoxue
authors.initials: B
authors.lastname: Yang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D004912:Erythrocytes / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006860:Hydrogen Bonding; D026901:Membrane Transport Proteins / Q000737:chemistry*; D051379:Mice; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D000096982:Urea Transporters
chemical_list: D026901:Membrane Transport Proteins; D000096982:Urea Transporters