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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.
AuthorsGeorg Sager, Elin Ø Ørvoll, Roy A Lysaa, Irina Kufareva, Ruben Abagyan, Aina W Ravna
JournalJournal of medicinal chemistry (J Med Chem) Vol. 55 Issue 7 Pg. 3049-57 (Apr 12 2012) ISSN: 1520-4804 [Electronic] United States
PMID22380603 (Publication Type: Journal Article)
Copyright© 2012 American Chemical Society
Chemical References
  • ABCC5 protein, human
  • Ligands
  • Multidrug Resistance-Associated Proteins
  • Piperazines
  • Purines
  • Sulfones
  • Sildenafil Citrate
  • Cyclic GMP
Topics
  • Amino Acid Sequence
  • Animals
  • Cyclic GMP (antagonists & inhibitors, metabolism)
  • Databases, Factual
  • Erythrocyte Membrane (drug effects, metabolism, ultrastructure)
  • Humans
  • Ligands
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Multidrug Resistance-Associated Proteins (antagonists & inhibitors)
  • Piperazines (chemistry)
  • Protein Binding
  • Purines (chemistry)
  • Sequence Alignment
  • Sildenafil Citrate
  • Structure-Activity Relationship
  • Sulfones (chemistry)

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