title: Inhibitor Discovery for the Human GLUT1 from Homology Modeling and Virtual Screening.
abstract: The human Glucose Transporter 1 (hGLUT1 or SLC2A1) is a facilitative membrane transporter found in the liver, intestines, kidney, and brain, where it transports sugars such as d-glucose and d-galactose. Genetic variations in hGLUT1 are associated with a broad range of diseases and metabolic disorders. For example, hGLUT1 is upregulated in various cancer types (e.g., breast carcinoma) to support the increased anaerobic glycolysis and the Warburg effect. Thus, hGLUT1 is an emerging therapeutic target, which also transports commonly used cancer biomarkers (e.g., (18)F-DG). In this study, we use computational prediction followed by experimental testing, to characterize hGLUT1. We construct homology models of hGLUT1 in a partially occluded outward open ("occluded") conformation based on the X-ray structure of the E. coli xylose transporter, XylE. Comparison of the binding site of the occluded models to experimentally determined hGLUT structures revealed a hydrophobic pocket adjacent to the sugar-binding site, which was tested experimentally via site-directed mutagenesis. Virtual screening of various libraries of purchasable compounds against the occluded models, followed by experimental testing with cellular assays revealed seven previously unknown hGLUT1 ligands with IC50 values ranging from 0.45 μM to 59 μM. These ligands represent three unique chemotypes that are chemically different from any other known hGLUT1 ligands. The newly characterized hydrophobic pocket can potentially be utilized by the new ligands for increased affinity. Furthermore, the previously unknown hGLUT1 ligands can serve as chemical tools to further characterize hGLUT1 function or lead molecules for future drug development.
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
authors.forename: Peter Man-Un
authors.initials: PM
authors.lastname: Ung
authors.affiliation: School of Pharmaceutical Sciences, Tsinghua University , Beijing, China 100084.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Song
authors.affiliation: School of Pharmaceutical Sciences, Tsinghua University , Beijing, China 100084.
authors.forename: Lili
authors.initials: L
authors.lastname: Cheng
authors.affiliation: School of Pharmaceutical Sciences, Tsinghua University , Beijing, China 100084.
authors.forename: Xinbin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: School of Pharmaceutical Sciences, Tsinghua University , Beijing, China 100084.
authors.forename: Hailin
authors.initials: H
authors.lastname: Hu
authors.affiliation: School of Pharmaceutical Sciences, Tsinghua University , Beijing, China 100084.
authors.forename: Ligong
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.|Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
authors.forename: Avner
authors.initials: A
authors.lastname: Schlessinger
mesh_terms: D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation
chemical_list: D051272:Glucose Transporter Type 1; C495677:SLC2A1 protein, human