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Per Artursson - One of the best experts on this subject based on the ideXlab platform.

  • structural requirements for drug inhibition of the liver specific human organic cation Transport Protein 1
    Journal of Medicinal Chemistry, 2008
    Co-Authors: Gustav Ahlin, Lena Gustavsson, Pär Matsson, Jenny M. Pedersen, Rolf Larsson, Ulf Norinder, Christel A. S. Bergström, Johan Karlsson, Per Artursson
    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. I ...

  • structural requirements for drug inhibition of the liver specific human organic cation Transport Protein 1
    Journal of Medicinal Chemistry, 2008
    Co-Authors: Gustav Ahlin, Lena Gustavsson, Pär Matsson, Jenny M. Pedersen, Rolf Larsson, Ulf Norinder, Christel A. S. Bergström, Johan Karlsson, Per Artursson
    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.

Jeffrey H Miner - One of the best experts on this subject based on the ideXlab platform.

  • Fatty acid Transport Protein 4 is required for incorporation of saturated ultralong-chain fatty acids into epidermal ceramides and monoacylglycerols
    Scientific Reports, 2019
    Co-Authors: Meei-hua Lin, Fong-fu Hsu, Jason Meyer, Debra Crumrine, Jeffrey H Miner
    Abstract:

    Fatty acid Transport Protein 4 (FATP4) is an acyl-CoA synthetase that is required for normal permeability barrier in mammalian skin. FATP4 ( SLC27A4 ) mutations cause ichthyosis prematurity syndrome, a nonlethal disorder. In contrast, Fatp4 ^−/− mice die neonatally from a defective barrier. Here we used electron microscopy and lipidomics to characterize defects in Fatp4 ^−/− mice. Mutants showed lamellar body, corneocyte lipid envelope, and cornified envelope abnormalities. Lipidomics identified two lipids previously speculated to be present in mouse epidermis, sphingosine β-hydroxyceramide and monoacylglycerol; mutants displayed decreased proportions of these and the two ceramide classes that carry ultralong-chain, amide-linked fatty acids (FAs) thought to be critical for barrier function, unbound ω-O-acylceramide and bound ω-hydroxyceramide, the latter constituting the major component of the corneocyte lipid envelope. Other abnormalities included elevated amounts of sphingosine α-hydroxyceramide, phytosphingosine non-hydroxyceramide, and 1-O-acylceramide. Acyl chain length alterations in ceramides also suggested roles for FATP4 in esterifying saturated non-hydroxy and β-hydroxy FAs with at least 25 carbons and saturated or unsaturated ω-hydroxy FAs with at least 30 carbons to CoA. Our lipidomic analysis is the most thorough such study of the Fatp4 ^−/− mouse skin barrier to date, providing information about how FATP4 can contribute to barrier function by regulating fatty acyl moieties in various barrier lipids.

  • fatty acid Transport Protein 4 fatp4 prevents light induced degeneration of cone and rod photoreceptors by inhibiting rpe65 isomerase
    The Journal of Neuroscience, 2013
    Co-Authors: Jungsoo Lee, Jeffrey H Miner, William C Gordon, Nicolas G Bazan, Yongdong Zhou, James M Hill, Minghao Jin
    Abstract:

    Although rhodopsin is essential for sensing light for vision, it also mediates light-induced apoptosis of photoreceptors in mouse. RPE65, which catalyzes isomerization of all-trans retinyl fatty acid esters to 11-cis-retinol (11cROL) in the visual cycle, controls the rhodopsin regeneration rate and photoreceptor susceptibility to light-induced degeneration. Mutations in RPE65 have been linked to blindness in affected children. Despite such importance, the mechanism that regulates RPE65 function remains unclear. Through unbiased expression screening of a bovine retinal pigment epithelium (RPE) cDNA library, we have identified elongation of very long-chain fatty acids-like 1 (ELOVL1) and fatty acid Transport Protein 4 (FATP4), which each have very long-chain fatty acid acyl-CoA synthetase (VLCFA-ACS) activity, as negative regulators of RPE65. We found that the VLCFA derivative lignoceroyl (C24:0)-CoA inhibited synthesis of 11cROL, whereas palmitoyl (C16:0)-CoA promoted synthesis of 11cROL. We further found that competition of FATP4 with RPE65 for the substrate of RPE65 was also involved in the mechanisms by which FATP4 inhibits synthesis of 11cROL. FATP4 was predominantly expressed in RPE, and the FATP4-deficient RPE showed significantly higher isomerase activity. Consistent with these results, the regeneration rate of 11-cis-retinaldehyde and the recovery rate for rod light sensitivity were faster in FATP4-deficient mice than wild-type mice. Moreover, FATP4-deficient mice displayed increased accumulation of the cytotoxic all-trans retinaldehyde and hypersusceptibility to light-induced photoreceptor degeneration. Our findings demonstrate that ELOVL1, FATP4, and their products comprise the regulatory elements of RPE65 and play important roles in protecting photoreceptors from degeneration induced by light damage.

  • fatty acid Transport Protein 4 is dispensable for intestinal lipid absorption in mice
    Journal of Lipid Research, 2009
    Co-Authors: Jien Shim, Meei-hua Lin, Jeffrey H Miner, Casey L. Moulson, Yan Xie, Elizabeth P Newberry, Susan Kennedy, Nicholas O. Davidson
    Abstract:

    FA Transport Protein 4 (FATP4), one member of a multigene family of FA Transporters, was proposed as a major FA Transporter in intestinal lipid absorption. Due to the fact that Fatp4−/− mice die because of a perinatal skin defect, we rescued the skin phenotype using an FATP4 transgene driven by a keratinocyte-specific promoter (Fatp4−/−;Ivl-Fatp4tg/+ mice) to elucidate the role of intestinal FATP4 in dietary lipid absorption. Fatp4−/−;Ivl-Fatp4tg/+ mice and wild-type littermates displayed indistinguishable food consumption, growth, and weight gain on either low or high fat (Western) diets, with no differences in intestinal triglyceride (TG) absorption or fecal fat losses. Cholesterol absorption and intestinal TG absorption kinetics were indistinguishable between the genotypes, although Western diet fed Fatp4−/−;Ivl-Fatp4tg/+ mice showed a significant increase in enterocyte TG and FA content. There was no compensatory upregulation of other FATP family members or any other FA or cholesterol Transporters in Fatp4−/−;Ivl-Fatp4tg/+ mice. Furthermore, although serum cholesterol levels were lower in Fatp4−/−;Ivl-Fatp4tg/+ mice, there was no difference in hepatic VLDL secretion in-vivo or in hepatic lipid content on either a chow or Western diet. Taken together, our studies find no evidence for a physiological role of intestinal FATP4 in dietary lipid absorption in mice.

  • keratinocyte specific expression of fatty acid Transport Protein 4 rescues the wrinkle free phenotype in slc27a4 fatp4 mutant mice
    Journal of Biological Chemistry, 2007
    Co-Authors: Casey L. Moulson, Meei-hua Lin, Nicholas O. Davidson, Elizabeth P Newberry, Michael J White, Jeffrey H Miner
    Abstract:

    FATP4 (fatty acid Transport Protein 4; also known as SLC27A4) is the most widely expressed member of a family of six long chain fatty acid Transporters. FATP4 is highly expressed in enterocytes and has therefore been proposed to be a major importer of dietary fatty acids. Two independent mutations in Fatp4 cause mice to be born with thick, tight, shiny, "wrinkle-free" skin and a defective skin barrier; they die within hours of birth from dehydration and restricted movements. In contrast, induced keratinocyte-specific deficiency of FATP4 in adult mice causes only mild skin abnormalities. Therefore, whether the loss of FATP4 from skin or a systemic gestational metabolic defect causes the severe skin defects and neonatal lethality remain important unanswered questions. To investigate the basis for the phenotype, we first generated wild-type tetraploid/mutant diploid aggregates that should lead to rescue of any abnormalities caused by loss of FATP4 from the placenta. However, the skin phenotype was not ameliorated. We then generated transgenic mice expressing exogenous FATP4 either widely or specifically in suprabasal keratinocytes, and we bred the transgenes onto the Fatp4(-/-) background. Both modes of FATP4 expression led to rescue of the neonatally lethal skin defects, and the resulting mice were viable and fertile. Keratinocyte expression of an FATP4 variant with mutations in the acyl-CoA synthetase domain did not provide any degree of rescue. We conclude that expression of FATP4 with an intact acyl-CoA synthetase domain in suprabasal keratinocytes is necessary for normal skin development and that FATP4 functions in establishing the cornified envelope.

  • Cloning of wrinkle-free, a previously uncharacterized mouse mutation, reveals crucial roles for fatty acid Transport Protein 4 in skin and hair development
    Proceedings of the National Academy of Sciences of the United States of America, 2003
    Co-Authors: Casey L. Moulson, Daniel R. Martin, Jesse J. Lugus, Jean E. Schaffer, Anne C. Lind, Jeffrey H Miner
    Abstract:

    Wrinkle-free (wrfr) is a previously uncharacterized, spontaneous, autosomal recessive mouse mutation resulting in very tight, thick skin. wrfr mutant mice exhibit severe breathing difficulties secondary to their tight skin and die shortly after birth. This phenotype is strikingly similar to a very rare human genetic disorder, restrictive dermopathy. wrfr mutant mice display a defective skin barrier, which is normally imparted by the cornified envelope, a composite of Protein and lipid that prevents loss of water from within and entry of potentially harmful substances from without. In addition, hair growth from grafted wrfr skin is impaired. Positional cloning of the wrfr mutation revealed a retrotransposon insertion into a coding exon of Slc27a4, the gene encoding fatty acid Transport Protein (FATP)4. FATP4 is the primary intestinal FATP and is thought to play a major role in dietary fatty acid uptake; it therefore is viewed as a target to prevent or reverse obesity. However, its function in vivo had not been determined. Our results demonstrate an unexpected yet critical role for FATP4 in skin and hair development and suggest Slc27a4 to be a candidate gene for restrictive dermopathy.

Kentaro Hanada - One of the best experts on this subject based on the ideXlab platform.

  • three component one pot tandem sonogashira suzuki miyaura coupling reactions for the synthesis of a library of ceramide Transport Protein inhibitors designed in silico
    Asian Journal of Organic Chemistry, 2020
    Co-Authors: Kentaro Hanada, Masaharu Ueno, Norikazu Miyoshi, Shū Kobayashi
    Abstract:

    We have developed a one-pot, tandem Sonogashira/Suzuki–Miyaura coupling reaction, which is unknown synthetically, and applied it for the synthesis of a library of potential natural ligand nonmimetic inhibitors of the lipid-transfer Protein, ceramide-Transport Protein (CERT). The characteristic feature of this reaction is that the two-step coupling reaction proceeds smoothly with only 5 mol% of palladium catalyst. Furthermore, the location of the formed carbon–carbon bond would be strictly defined because of the difference in reactivity. Therefore, many derivatives could be synthesized in high yields without the formation of regioisomeric byproducts by the same procedure. We also performed a semi-gram scale synthesis of several derivatives to provide the bioactive assey. After synthesizing as many as 113 derivatives, we identified a nonnatural mimetic inhibitor with activity comparable to that of the known inhibitor (1R,3S)-HPA-12.

  • co evolution of sphingomyelin and the ceramide Transport Protein cert
    Biochimica et Biophysica Acta, 2014
    Co-Authors: Kentaro Hanada
    Abstract:

    Life creates many varieties of lipids. The choline-containing sphingophospholipid sphingomyelin (SM) exists ubiquitously or widely in vertebrates and lower animals, but is absent or rare in bacteria, fungi, protists, and plants. In the biosynthesis of SM, ceramide, which is synthesized in the endoplasmic reticulum, is Transported to the Golgi region by the ceramide Transport Protein CERT, probably in a non-vesicular manner, and is then converted to SM by SM synthase, which catalyzes the reaction of phosphocholine transfer from phosphatidylcholine (PtdCho) to ceramide. Recent advances in genomics and lipidomics indicate that the phylogenetic occurrence of CERT and its orthologs is nearly parallel to that of SM. Based on the chemistry of lipids together with evolutionary aspects of SM and CERT, several concepts are here proposed. SM may serve as a chemically inert and robust, but non-covalently interactive lipid class at the outer leaflet of the plasma membrane. The functional domains and peptidic motifs of CERT are separated by exon units, suggesting an exon-shuffling mechanism for the generation of an ancestral CERT gene. CERT may have co-evolved with SM to bypass a competing metabolic reaction at the bifurcated point in the anabolism of ceramide. Human CERT is identical to the splicing variant of human Goodpasture antigen-binding Protein (GPBP) annotated as an extracellular non-canonical serine/threonine Protein kinase. The relationship between CERT and GPBP has also been discussed from an evolutionary aspect. Moreover, using an analogy of "compatible (or osmoprotective) solutes" that can accumulate to very high concentrations in the cytosol without denaturing Proteins, choline phospholipids such as PtdCho and SM may act as compatible phospholipids in biomembranes. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology.

  • Decreased ceramide Transport Protein (CERT) function alters sphingomyelin production following UVB irradiation.
    The Journal of biological chemistry, 2008
    Co-Authors: Alexandra Charruyer, Sean M. Bell, Miyuki Kawano, Sounthala Douangpanya, Ten-yang Yen, Bruce A. Macher, Keigo Kumagai, Kentaro Hanada, Walter M. Holleran, Yoshikazu Uchida
    Abstract:

    Increased cellular ceramide accounts in part for UVB irradiation-induced apoptosis in cultured human keratinocytes with concurrent increased glucosylceramide but not sphingomyelin generation in these cells. Given that conversion of ceramide to non-apoptotic metabolites such as sphingomyelin and glucosylceramide protects cells from ceramide-induced apoptosis, we hypothesized that failed up-regulation of sphingomyelin generation contributes to ceramide accumulation following UVB irradiation. Because both sphingomyelin synthase and glucosylceramide synthase activities were significantly decreased in UVB-irradiated keratinocytes, we investigated whether alteration(s) in the function of ceramide Transport Protein (or CERT) required for sphingomyelin synthesis occur(s) in UVB-irradiated cells. Fluorescently labeled N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)-d-erythro-sphingosine (C5-DMB-ceramide) relocation to the Golgi was diminished after irradiation, consistent with decreased CERT function, whereas the CERT inhibitor N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide (1R,3R isomer) (HPA-12) produced an equivalent effect. UVB irradiation also induced the rapid formation of a stable CERT homotrimer complex in keratinocytes as determined by Western immunoblot and mass spectrometry analyses, a finding replicated in HeLa, HEK293T, and HaCaT cells and in murine epidermis. Ceramide binding activity was decreased in recombinant CERT Proteins containing the UVB-induced homotrimer. The middle region domain of the CERT Protein was required for the homotrimer formation, whereas neither the pleckstrin homology (Golgi-binding) nor the START (ceramide-binding) domains were involved. Finally like UVB-treated keratinocytes, HPA-12 blockade of CERT function increased keratinocyte apoptosis, decreased sphingomyelin synthesis, and led to accumulation of ceramide. Thus, UVB-induced CERT homotrimer formation accounts, at least in part, for apoptosis and failed up-regulation of sphingomyelin synthesis following UVB irradiation, revealing that inactive CERT can attenuate a key metabolic protective mechanism against ceramide-induced apoptosis in keratinocytes.

  • Protein phosphatase 2cϵ is an endoplasmic reticulum integral membrane Protein that dephosphorylates the ceramide Transport Protein cert to enhance its association with organelle membranes
    Journal of Biological Chemistry, 2008
    Co-Authors: Satoko Saito, Miyuki Kawano, Keigo Kumagai, Kentaro Hanada, Hiroyuki Matsui, Nario Tomishige, Seishi Echigo, Shinri Tamura, Takayasu Kobayashi
    Abstract:

    Abstract Protein phosphatase 2Cϵ (PP2Cϵ), a mammalian PP2C family member, is expressed in various tissues and is implicated in the negative regulation of stress-activated Protein kinase pathways. We show that PP2Cϵ is an endoplasmic reticulum (ER) transmembrane Protein with a transmembrane domain at the amino terminus and the catalytic domain facing the cytoplasm. Yeast two-hybrid screening of a human brain library using PP2Cϵ as bait resulted in the isolation of a cDNA that encoded vesicle-associated membrane Protein-associated Protein A (VAPA). VAPA is an ER resident integral membrane Protein involved in recruiting lipid-binding Proteins such as the ceramide Transport Protein CERT to the ER membrane. Expression of PP2Cϵ resulted in dephosphorylation of CERT in a VAPA expression-dependent manner, which was accompanied by redistribution of CERT from the cytoplasm to the Golgi apparatus. The expression of PP2Cϵ also enhanced the association between CERT and VAPA. In addition, knockdown of PP2Cϵ expression by short interference RNA attenuated the interaction between CERT and VAPA and the sphingomyelin synthesis. These results suggest that CERT is a physiological substrate of PP2Cϵ and that dephosphorylation of CERT by PP2Cϵ may play an important role in the regulation of ceramide trafficking from the ER to the Golgi apparatus.

David A. Bernlohr - One of the best experts on this subject based on the ideXlab platform.

  • mouse fatty acid Transport Protein 4 fatp4 characterization of the gene and functional assessment as a very long chain acyl coa synthetase
    Gene, 2001
    Co-Authors: Thomas Herrmann, Isabella Gosch, Florian Buchkremer, David A. Bernlohr, Angela M Hall, W Stremmel
    Abstract:

    FATP4 (SLC27A4) is a member of the fatty acid Transport Protein (FATP) family, a group of evolutionarily conserved Proteins that are involved in cellular uptake and metabolism of long and very long chain fatty acids. We cloned and characterized the murine FATP4 gene and its cDNA. From database analysis we identified the human FATP4 genomic sequence. The FATP4 gene was assigned to mouse chromosome 2 band B, syntenic to the region 9q34 encompassing the human gene. The open reading frame was determined to be 1929 bp in length, encoding a polypeptide of 643 amino acids. Within the coding region, the exon-intron structures of the murine FATP4 gene and its human counterpart are identical, revealing a high similarity to the FATP1 gene. The overall amino acid identity between the deduced murine and human FATP4 polypeptides is 92.2%, and between the murine FATP1 and FATP4 polypeptides is 60.3%. Northern analysis showed that FATP4 mRNA was expressed most abundantly in small intestine, brain, kidney, liver, skin and heart. Transfection of FATP4 cDNA into COS1 cells resulted in a 2-fold increase in palmitoyl-CoA synthetase (C16:0) and a 5-fold increase in lignoceroyl-CoA synthetase (C24:0) activity from membrane extracts, indicating that the FATP4 gene encodes an acyl-CoA synthetase with substrate specificity biased towards very long chain fatty acids.

  • the fatty acid Transport Protein fatp1 is a very long chain acyl coa synthetase
    Journal of Biological Chemistry, 1999
    Co-Authors: Natalie Ribarik Coe, Paul A. Watkins, Anne J. Smith, Brigitte I Frohnert, David A. Bernlohr
    Abstract:

    The primary sequence of the murine fatty acid Transport Protein (FATP1) is very similar to the multigene family of very long chain (C20-C26) acyl-CoA synthetases. To determine if FATP1 is a long chain acyl coenzyme A synthetase, FATP1-Myc/His fusion Protein was expressed in COS1 cells, and its enzymatic activity was analyzed. In addition, mutations were generated in two domains conserved in acyl-CoA synthetases: a 6- amino acid substitution into the putative active site (amino acids 249-254) generating mutant M1 and a 59-amino acid deletion into a conserved C-terminal domain (amino acids 464-523) generating mutant M2. Immunolocalization revealed that the FATP1-Myc/His forms were distributed between the COS1 cell plasma membrane and intracellular membranes. COS1 cells expressing wild type FATP1-Myc/His exhibited a 3-fold increase in the ratio of lignoceroyl-CoA synthetase activity (C24:0) to palmitoyl-CoA synthetase activity (C16:0), characteristic of very long chain acyl-CoA synthetases, whereas both mutant M1 and M2 were catalytically inactive. Detergent-solubilized FATP1-Myc/His was partially purified using nickel-based affinity chromatography and demonstrated a 10-fold increase in very long chain acyl-CoA specific activity (C24:0/C16:0). These results indicate that FATP1 is a very long chain acyl-CoA synthetase and suggest that a potential mechanism for facilitating mammalian fatty acid uptake is via esterification coupled influx.

  • identification of a functional peroxisome proliferator responsive element in the murine fatty acid Transport Protein gene
    Journal of Biological Chemistry, 1999
    Co-Authors: Brigitte I Frohnert, To Y Hui, David A. Bernlohr
    Abstract:

    Fatty acid Transport Protein (FATP), a plasma membrane Protein implicated in controlling adipocyte transmembrane fatty acid flux, is up-regulated as a consequence of adipocyte differentiation and down-regulated by insulin. Based upon the sequence of the FATP gene upstream region (Hui, T. Y., Frohnert, B. I., Smith, A. J., Schaffer, J. A., and Bernlohr, D. A. (1998) J. Biol. Chem. 273, 27420–27429) a putative peroxisome proliferator-activated receptor response element (PPRE) is present from −458 to −474. To determine whether the FATP PPRE was functional, and responded to lipid activators, transient transfection of FATP-luciferase reporter constructs into CV-1 and 3T3-L1 cells was carried out. In CV-1 cells, FATP-luciferase activity was up-regulated 4- and 5.5-fold, respectively, by PPARα and PPARγ in the presence of their respective activators in a PPRE-dependent mechanism. PPARδ, however, was unable to mediate transcriptional activation under any condition. In 3T3-L1 cells, the PPRE conferred a small but significant increase in expression in preadipocytes, as well as a more robust up-regulation of FATP expression in adipocytes. Furthermore, the PPRE conferred the ability for luciferase expression to be up-regulated by activators of both PPARγ and retinoid X receptor α (RXRα) in a synergistic manner. PPARα and PPARδ activators did not up-regulate FATP expression in 3T3-L1 adipocytes, however, suggesting that these two subtypes do not play a significant role in differentiation-dependent activation in fat cells. Electromobility shift assays showed that all three PPAR subtypes were able to bind specifically to the PPRE as heterodimers with RXRα. Nuclear extracts from 3T3-L1 adipocytes also showed a specific gel-shift complex with the FATP PPRE. To correlate the expression of FATP to its physiological function, treatment of 3T3-L1 adipocytes with PPARγ and RXRα activators resulted in an increased uptake of oleate. Moreover, linoleic acid, a physiological ligand, up-regulated FATP expression 2-fold in a PPRE-dependent manner. These results demonstrate that the FATP gene possesses a functional PPRE and is up-regulated by activators of PPARα and PPARγ, thereby linking the activity of the Protein to the expression of its gene. Moreover, these results have implications for the mechanism by which certain PPARγ activators such as the antidiabetic thiazolidinedione drugs affect adipose lipid metabolism.

Gustav Ahlin - One of the best experts on this subject based on the ideXlab platform.

  • structural requirements for drug inhibition of the liver specific human organic cation Transport Protein 1
    Journal of Medicinal Chemistry, 2008
    Co-Authors: Gustav Ahlin, Lena Gustavsson, Pär Matsson, Jenny M. Pedersen, Rolf Larsson, Ulf Norinder, Christel A. S. Bergström, Johan Karlsson, Per Artursson
    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. I ...

  • structural requirements for drug inhibition of the liver specific human organic cation Transport Protein 1
    Journal of Medicinal Chemistry, 2008
    Co-Authors: Gustav Ahlin, Lena Gustavsson, Pär Matsson, Jenny M. Pedersen, Rolf Larsson, Ulf Norinder, Christel A. S. Bergström, Johan Karlsson, Per Artursson
    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.