title: Curcumin analogue identified as hyaluronan export inhibitor by virtual docking to the ABC transporter MRP5.
abstract: Hyaluronan is overproduced in many diseases including metastasis, inflammation or ischemia, but there is no drug to attenuate hyaluronan production. Hyaluronan is exported from fibroblasts by the multidrug resistance associated protein 5 (MRP5) which is inhibited by the plant phenols curcumin or xanthohumol. We performed virtual docking and chemical synthesis of analogues to optimize the inhibitors. The AutoDock software was used to identify the binding cavity within the open conformation of MRP5. Inhibitory plant phenols bound to the ATP binding site between the two nucleotide binding domains NBD1 and NBD2. This binding cavity was chosen to screen about 120 derivatives and analogues. The superior hyaluronan export inhibitor was 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one (hylin). It inhibited hyaluronan export from fibroblasts with an IC50 of 4.9 μM. Hylin is a minor component in natural curcumin preparations and has previously been described as anti-metastatic and anti-inflammatory. Since curcumin itself is unstable under physiological conditions, the active component for many cell biological and pharmaceutical effects of natural curcumin preparations could be hylin that acts by hyaluronan export inhibition.
authors: Muenster University Hospital, Institute of Physiological Chemistry and Pathobiochemistry, Waldeyerstrasse 15, D-48149 Muenster, Germany. Electronic address: prehm@uni-muenster.de.
authors: Peter
authors: P
authors: Prehm
mesh_terms: D001665:Binding Sites; D001692:Biological Transport / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives*; D005419:Flavonoids / Q000494:pharmacology; D006139:Guaiacol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D057809:HEK293 Cells / Q000187:drug effects; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D007659:Ketones / Q000378:metabolism / Q000494:pharmacology; D062105:Molecular Docking Simulation; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011427:Propiophenones / Q000494:pharmacology; D011487:Protein Conformation; D017434:Protein Structure, Tertiary
chemical_list: D003474:Curcumin; D005419:Flavonoids; D006139:Guaiacol; D006820:Hyaluronic Acid; D007659:Ketones; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011427:Propiophenones; C120809:ABCC5 protein, human; C000597748:hylin; C104536:xanthohumol
keywords: 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one; Extracellular matrix; HEK; Hyaluronan export inhibitor; Hylin; MRP5; NBD; Plasma membrane; Virtual docking; human embryonic kidney; multidrug resistance associated protein 5; nucleotide binding domain