Journal
CURRENT TOPICS IN MEDICINAL CHEMISTRY
Volume 13, Issue 7, Pages 843-856Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1568026611313070007
Keywords
Membrane transporter; comparative modeling; ligand docking; protein function prediction; structure-based ligand discovery
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Funding
- National Institutes of Health [R01 GM54762, U54 GM074929, P01 GM71790, U01 GM61390]
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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.
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