Molecular Modeling and Ligand Docking for Solute Carrier (SLC) Transporters
Avner Schlessinger, Natalia Khuri, Kathleen M. Giacomini and Andrej Sali
Affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, 1700 4th Street, San Francisco, CA 94158.
Solute Carrier (SLC) transporters are membrane proteins that transport solutes, such as ions, metabolites, peptides,
and drugs, across biological membranes, using diverse energy coupling mechanisms. In human, there are 386 SLC
transporters, many of which contribute to the absorption, distribution, metabolism, and excretion of drugs and/or can be
targeted directly by therapeutics. Recent atomic structures of SLC transporters determined by X-ray crystallography and
NMR spectroscopy have significantly expanded the applicability of structure-based prediction of SLC transporter ligands,
by enabling both comparative modeling of additional SLC transporters and virtual screening of small molecules libraries
against experimental structures as well as comparative models. In this review, we begin by describing computational
tools, including sequence analysis, comparative modeling, and virtual screening, that are used to predict the structures and
functions of membrane proteins such as SLC transporters. We then illustrate the applications of these tools to predicting
ligand specificities of select SLC transporters, followed by experimental validation using uptake kinetic measurements
and other assays. We conclude by discussing future directions in the discovery of the SLC transporter ligands.
Keywords: Membrane transporter, comparative modeling, ligand docking, protein function prediction, structure-based ligand
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