Molecular modeling and ligand docking for solute carrier (SLC) transporters

Avner Schlessinger, Natalia Khuri, Kathleen M. Giacomini, Andrej Sali

Research output: Contribution to journalReview articlepeer-review

64 Scopus citations

Abstract

Solute Carrier (SLC) transporters are membrane proteins that transport solutes, such as ions, metabolites, pep-tides, 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.

Original languageEnglish
Pages (from-to)843-856
Number of pages14
JournalCurrent Topics in Medicinal Chemistry
Volume13
Issue number6 7
DOIs
StatePublished - 2013

Keywords

  • Comparative modeling
  • Ligand docking
  • Membrane transporter
  • Protein function prediction
  • Structure-based ligand discovery

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