AI Article Synopsis
- OCT1 is essential for liver cells to take up various compounds, including drugs and natural substances.
- Researchers screened a library of 1780 prescription drugs using computer modeling and lab tests to find ligands that interact with OCT1.
- The study identified 30 competitive ligands and highlighted that 5 could potentially cause drug interactions, including 146 additional ligands found in metabolites, with one specific neurotoxin validated.
Article 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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| http://dx.doi.org/10.1021/acs.jmedchem.6b01317 | DOI Listing |
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