Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Article Details
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Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergstrom CA, Artursson P
Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
J Med Chem. 2008 Oct 9;51(19):5932-42. doi: 10.1021/jm8003152. Epub 2008 Sep 13.
- PubMed ID
- 18788725 [ View in PubMed]
- Abstract
The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Imatinib Solute carrier family 22 member 1 Protein Humans NoSubstrateDetails Metformin Solute carrier family 22 member 1 Protein Humans UnknownSubstrateDetails - Binding Properties
Drug Target Property Measurement pH Temperature (°C) Desipramine Solute carrier family 22 member 1 IC 50 (nM) 56800 N/A N/A Details Disopyramide Solute carrier family 22 member 1 IC 50 (nM) 81700 N/A N/A Details Phenoxybenzamine Solute carrier family 22 member 1 IC 50 (nM) 15100 N/A N/A Details Prazosin Solute carrier family 22 member 1 IC 50 (nM) 9900 N/A N/A Details Quinidine Solute carrier family 22 member 1 IC 50 (nM) 113800 N/A N/A Details Quinine Solute carrier family 22 member 1 IC 50 (nM) 51600 N/A N/A Details Verapamil Solute carrier family 22 member 1 IC 50 (nM) 6800 N/A N/A Details - Drug Interactions
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