Structural Requirements for Drug Inhibition of the Liver Specific Human Organic Cation Transport Protein 1

详细信息    查看全文

• 作者：Gustav Ahlin ; Johan Karlsson ; Jenny M. Pedersen ; Lena Gustavsson ; Rolf Larsson ; Pä ; r Matsson ; Ulf Norinder ; Christel A. S. Bergströ ; m ; Per Artursson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：October 9, 2008
• 年：2008
• 卷：51
• 期：19
• 页码：5932-5942
• 全文大小：428K
• 年卷期：v.51,no.19(October 9, 2008)
• ISSN：1520-4804

文摘

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.