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

作者：Chen Eugene C; Khuri Natalia; Liang Xiaomin; Stecula Adrian; Chien Huan Chieh; Yee Sook Wah; Huang Yong; Sali Andrej; Giacomini Kathleen M^*

来源：Journal of Medicinal Chemistry, 2017, 60(7): 2685-2696.

DOI：10.1021/acs.jmedchem.6b01317

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.

• 出版日期2017-4-13