2. Academic Validation
  3. Discovery of Competitive and Noncompetitive Ligands of the Organic Cation Transporter 1 (OCT1; SLC22A1)

Discovery of Competitive and Noncompetitive Ligands of the Organic Cation Transporter 1 (OCT1; SLC22A1)

  • J Med Chem. 2017 Apr 13;60(7):2685-2696. doi: 10.1021/acs.jmedchem.6b01317.
Eugene C Chen 1,  Natalia Khuri 1,  Xiaomin Liang 1,  Adrian Stecula 1,  Huan-Chieh Chien 1,  Sook Wah Yee 1,  Yong Huang 2,  Andrej Sali 1 3 4,  Kathleen M Giacomini 1 3 4 5
Affiliations

Affiliations

  • 1 Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, California 94143, United States.
  • 2 Optivia Biotechnology , Menlo Park, California 94025, United States.
  • 3 Department of Pharmaceutical Chemistry, University of California , San Francisco, California 94158, United States.
  • 4 California Institute of Quantitative Biosciences, University of California , San Francisco, California 94158, United States.
  • 5 Institute of Human Genetics, University of California , San Francisco, California 94143, United States.
PMID: 28230985 DOI: 10.1021/acs.jmedchem.6b01317
Abstract

Organic cation transporter 1 (OCT1) plays a critical role in the hepatocellular uptake of structurally diverse endogenous compounds and xenobiotics. Here we identified competitive and noncompetitive OCT1-interacting ligands in a library of 1780 prescription drugs by combining in silico and in vitro methods. Ligands were predicted by docking against a comparative model based on a eukaryotic homologue. In parallel, high-throughput screening (HTS) was conducted using the fluorescent probe substrate ASP+ in cells overexpressing human OCT1. Thirty competitive OCT1 ligands, defined as ligands predicted in silico as well as found by HTS, were identified. Of the 167 ligands identified by HTS, five were predicted to potentially cause clinical drug interactions. Finally, virtual screening of 29 332 metabolites predicted 146 competitive OCT1 ligands, of which an endogenous neurotoxin, 1-benzyl-1,2,3,4-tetrahydroisoquinoline, was experimentally validated. In conclusion, by combining docking and in vitro HTS, competitive and noncompetitive ligands of OCT1 can be predicted.

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