title: Discovery of Competitive and Noncompetitive Ligands of the Organic Cation Transporter 1 (OCT1; SLC22A1).
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.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, California 94143, United States.
authors.forename: Eugene C
authors.initials: EC
authors.lastname: Chen
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, California 94143, United States.
authors.forename: Natalia
authors.identifier: 0000-0001-9031-8124
authors.initials: N
authors.lastname: Khuri
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, California 94143, United States.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, California 94143, United States.
authors.forename: Adrian
authors.initials: A
authors.lastname: Stecula
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, California 94143, United States.
authors.forename: Huan-Chieh
authors.initials: HC
authors.lastname: Chien
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, California 94143, United States.
authors.forename: Sook Wah
authors.initials: SW
authors.lastname: Yee
authors.affiliation: Optivia Biotechnology , Menlo Park, California 94025, United States.
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, California 94143, United States.|Department of Pharmaceutical Chemistry, University of California , San Francisco, California 94158, United States.|California Institute of Quantitative Biosciences, University of California , San Francisco, California 94158, United States.
authors.forename: Andrej
authors.identifier: 0000-0003-0435-6197
authors.initials: A
authors.lastname: Sali
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, California 94143, United States.|Department of Pharmaceutical Chemistry, University of California , San Francisco, California 94158, United States.|California Institute of Quantitative Biosciences, University of California , San Francisco, California 94158, United States.|Institute of Human Genetics, University of California , San Francisco, California 94143, United States.
authors.forename: Kathleen M
authors.identifier: 0000-0001-8041-5430
authors.initials: KM
authors.lastname: Giacomini
mesh_terms: D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D027702:Organic Cation Transporter 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D008024:Ligands; D027702:Organic Cation Transporter 1; D054852:Small Molecule Libraries