Chen Eugene C, Khuri Natalia, Liang Xiaomin, Stecula Adrian, Chien Huan-Chieh, Yee Sook Wah, Huang Yong, Sali Andrej, Giacomini Kathleen M
Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, California 94143, United States.
Optivia Biotechnology , Menlo Park, California 94025, United States.
J Med Chem. 2017 Apr 13;60(7):2685-2696. doi: 10.1021/acs.jmedchem.6b01317. Epub 2017 Mar 15.
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.
有机阳离子转运体1（OCT1）在肝细胞摄取结构多样的内源性化合物和外源性物质过程中发挥着关键作用。在此，我们通过结合计算机模拟和体外实验方法，在一个包含1780种处方药的文库中鉴定出了竞争性和非竞争性的OCT1相互作用配体。通过与基于真核同源物的比较模型进行对接来预测配体。同时，在过表达人OCT1的细胞中使用荧光探针底物ASP进行高通量筛选（HTS）。鉴定出了30种竞争性OCT1配体，即通过计算机模拟预测并经HTS发现的配体。在HTS鉴定出的167种配体中，有5种被预测可能会引起临床药物相互作用。最后，对29332种代谢产物进行虚拟筛选，预测出146种竞争性OCT1配体，其中一种内源性神经毒素1-苄基-1,2,3,4-四氢异喹啉经实验验证。总之，通过结合对接和体外HTS，可以预测OCT1的竞争性和非竞争性配体。
