title: Discovery of a specific inhibitor of human GLUT5 by virtual screening and in vitro transport evaluation.
abstract: GLUT5, a fructose-transporting member of the facilitative glucose transporter (GLUT, SLC2) family, is a therapeutic target for diabetes and cancer but has no potent inhibitors. We virtually screened a library of 6 million chemicals onto a GLUT5 model and identified N-[4-(methylsulfonyl)-2-nitrophenyl]-1,3-benzodioxol-5-amine (MSNBA) as an inhibitor of GLUT5 fructose transport in proteoliposomes. MSNBA inhibition was specific to GLUT5; this inhibitor did not affect the fructose transport of human GLUT2 or the glucose transport of human GLUT1-4 or bacterial GlcPSe. In MCF7 cells, a human breast cancer cell line, MSNBA competitively inhibited GLUT5 fructose uptake with a KI of 3.2 ± 0.4 μM. Ligand docking, mutagenesis and functional studies indicate that MSNBA binds near the active site and inhibitor discrimination involves H387 of GLUT5. Thus, MSNBA is a selective and potent inhibitor of fructose transport via GLUT5, and the first chemical probe for this transporter. Our data indicate that active site differences in GLUT members could be exploited to further enhance ligand specificity.
authors.affiliation: Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, 3333 Green Bay Road, North Chicago, IL, 60064, USA.
authors.forename: Alayna M
authors.initials: AM
authors.lastname: George Thompson
authors.affiliation: Department of Internal Medicine, Translational Informatics Division, MSC09 5025, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
authors.forename: Oleg
authors.initials: O
authors.lastname: Ursu
authors.affiliation: Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, 3333 Green Bay Road, North Chicago, IL, 60064, USA.
authors.forename: Petr
authors.initials: P
authors.lastname: Babkin
authors.affiliation: Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, 3333 Green Bay Road, North Chicago, IL, 60064, USA.
authors.forename: Cristina V
authors.initials: CV
authors.lastname: Iancu
authors.affiliation: Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, 3333 Green Bay Road, North Chicago, IL, 60064, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Whang
authors.affiliation: Department of Internal Medicine, Translational Informatics Division, MSC09 5025, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
authors.forename: Tudor I
authors.initials: TI
authors.lastname: Oprea
authors.affiliation: Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, 3333 Green Bay Road, North Chicago, IL, 60064, USA.
authors.forename: Jun-yong
authors.initials: JY
authors.lastname: Choe
mesh_terms: D001692:Biological Transport / Q000187:drug effects; D020134:Catalytic Domain; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000302:isolation & purification*; D005632:Fructose / Q000378:metabolism; D051296:Glucose Transporter Type 5 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D056004:Molecular Dynamics Simulation; D016296:Mutagenesis; D011485:Protein Binding
chemical_list: D004791:Enzyme Inhibitors; D051296:Glucose Transporter Type 5; C495726:SLC2A5 protein, human; D005632:Fructose