title: Novel cGMP efflux inhibitors identified by virtual ligand screening (VLS) and confirmed by experimental studies.
abstract: Elevated intracellular levels of cyclic guanosine monophosphate (cGMP) may induce apoptosis, and at least some cancer cells seem to escape this effect by increased efflux of cGMP, as clinical studies have shown that extracellular cGMP levels are elevated in various types of cancer. The human ATP binding cassette (ABC) transporter ABCC5 transports cGMP out of cells, and inhibition of ABCC5 may have cytotoxic effects. Sildenafil inhibits cGMP efflux by binding to ABCC5, and in order to search for potential novel ABCC5 inhibitors, we have identified sildenafil derivates using structural and computational guidance and tested them for the cGMP efflux effect. Eleven compounds from virtual ligand screening (VLS) were tested in vitro, using inside-out vesicles (IOV), for inhibition of cGMP efflux. Seven of 11 compounds predicted by VLS to bind to ABCC5 were more potent than sildenafil, and the two most potent showed K(i) of 50-100 nM.
authors.affiliation: Medical Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, 9037 Tromsø, Norway.
authors.forename: Georg
authors.initials: G
authors.lastname: Sager
authors.forename: Elin Ø
authors.initials: EØ
authors.lastname: Ørvoll
authors.forename: Roy A
authors.initials: RA
authors.lastname: Lysaa
authors.forename: Irina
authors.initials: I
authors.lastname: Kufareva
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.forename: Aina W
authors.initials: AW
authors.lastname: Ravna
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006152:Cyclic GMP / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016208:Databases, Factual; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000737:chemistry*; D011485:Protein Binding; D011687:Purines / Q000737:chemistry; D016415:Sequence Alignment; D000068677:Sildenafil Citrate; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry*
chemical_list: D006152:Cyclic GMP; D008024:Ligands; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010879:Piperazines; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; C120809:ABCC5 protein, human