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Structure‐based ligand discovery for nutrient transporters
Author(s) -
Schlessinger Avner
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb486
Subject(s) - transporter , glut1 , solute carrier family , drug discovery , biology , glucose transporter , cancer cell , small molecule , microbiology and biotechnology , chemistry , computational biology , biochemistry , cancer , gene , genetics , endocrinology , insulin
Alterations in cell metabolism support rapid growth and proliferation of cells ‐ key hallmarks of cancer. Solute Carrier (SLC) transporters are membrane proteins that transport solutes such as metabolites and drugs across membranes, and play a major role in mediating nutrient delivery in reprogrammed cancer metabolism networks. Here, we describe a structure‐based discovery approach to identify small molecule modulators for key nutrient SLC transporters. In particular, we use homology modeling, virtual screening, and experimental testing to identify small molecule ligands including drugs, metabolites, and lead‐like molecules. We target a variety of nutrient transporters such as the amino acid transporters LAT‐1 and ASCT2, and the glucose transporter GLUT1, which function cooperatively in cancer metabolism and are highly expressed in the blood‐brain‐barrier (BBB). Our results may explain some of the pharmacological effects (i.e., efficacy and/or side effects) of known drugs via polypharmacology, and rationalize the enhanced brain permeability of drug‐like molecules. Finally, our top hits inhibited proliferation of various cancer cell lines via distinct molecular mechanisms, providing useful chemical tools to characterize reprogrammed metabolic networks, as well as a framework for developing efficacious drugs against these key targets and other SLC transporters. Support or Funding Information R01 GM108911