Solute Carrier (SLC) transporters can play a major role in mediating nutrient delivery in reprogrammed cancer metabolism networks. For example, the amino acid transporters LAT1 (SLC7A5) and ASCT2 (SLC1A5) are upregulated in a variety of cancer types, where they supply the growing tumor cells with essential amino acids that are used as nutrients to build biomass and signaling molecules to enhance proliferation. Here, we apply a range of computational modeling methods, including homology modeling, ligand docking, and MD simulations to develop strategies to modulate nutrient SLC transporters. Specifically, we use homology modeling to model human SLCs in previously uncharacterized, pharmacologically relevant conformations. We then use virtual screening and functional testing to identify conformation-specific inhibitors. Initial hits are then refined through iteration of computational modeling and medicinal chemistry as well as biochemical and structural approaches. Our results provide useful chemical tools to characterize reprogrammed metabolic networks, as well as a framework for developing efficacious lead compounds against these key targets and other SLC transporters.<br/>

Targeting pharmacologically relevant conformations of SLC transporters

ACS Fall 2020 Virtual Meeting

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