title: Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
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.
authors.affiliation: Department of Pharmacy, Uppsala University, Uppsala, Sweden.
authors.forename: Gustav
authors.initials: G
authors.lastname: Ahlin
authors.forename: Johan
authors.initials: J
authors.lastname: Karlsson
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Pedersen
authors.forename: Lena
authors.initials: L
authors.lastname: Gustavsson
authors.forename: Rolf
authors.initials: R
authors.lastname: Larsson
authors.forename: Pär
authors.initials: P
authors.lastname: Matsson
authors.forename: Ulf
authors.initials: U
authors.lastname: Norinder
authors.forename: Christel A S
authors.initials: CA
authors.lastname: Bergström
authors.forename: Per
authors.initials: P
authors.lastname: Artursson
mesh_terms: D002460:Cell Line; D003198:Computer Simulation; D015195:Drug Design; D020869:Gene Expression Profiling; D006801:Humans; D006860:Hydrogen Bonding; D008099:Liver / Q000737:chemistry*; D008970:Molecular Weight; D027702:Organic Cation Transporter 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship
chemical_list: D027702:Organic Cation Transporter 1; D004364:Pharmaceutical Preparations; D012333:RNA, Messenger