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Synthesis and Assay of Vibrio Quorum Sensing Inhibitors
Published on: May 31, 2024
Novel cGMP efflux inhibitors identified by virtual ligand screening (VLS) and confirmed by experimental studies
Georg Sager1, Elin Ø Ørvoll, Roy A Lysaa
1Medical Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, 9037 Tromsø, Norway.
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.
Insights
Novel sildenafil derivatives were identified to inhibit cyclic guanosine monophosphate (cGMP) efflux by targeting the ABCC5 transporter. These compounds show potential as novel cancer therapeutics by increasing cytotoxic cGMP levels in cancer cells.
Area of Science:
- Biochemistry
- Pharmacology
- Cancer Biology
Background:
- Elevated intracellular cyclic guanosine monophosphate (cGMP) can induce apoptosis.
- Cancer cells may evade apoptosis by increasing cGMP efflux, leading to higher extracellular cGMP levels in tumors.
- The ATP binding cassette (ABC) transporter ABCC5 facilitates cGMP efflux, making it a potential therapeutic target.
Purpose of the Study:
- To identify novel inhibitors of the ABCC5 transporter.
- To discover new compounds that can block cGMP efflux from cancer cells.
- To evaluate the potential of these inhibitors as anti-cancer agents.
Main Methods:
- Utilized structural and computational guidance to design sildenafil derivatives.
- Employed virtual ligand screening (VLS) to predict compounds binding to ABCC5.
- Tested eleven VLS-identified compounds in vitro using inside-out vesicles (IOV) to assess cGMP efflux inhibition.
Main Results:
- Seven out of eleven tested compounds demonstrated greater potency in inhibiting cGMP efflux than sildenafil.
- The two most potent novel compounds exhibited inhibition constants (K(i)) in the range of 50-100 nM.
- These results validate the VLS approach for identifying ABCC5 inhibitors.
Conclusions:
- Novel sildenafil derivatives effectively inhibit ABCC5-mediated cGMP efflux.
- These identified compounds represent promising candidates for developing new cancer therapies.
- Targeting ABCC5 with potent inhibitors could restore cGMP-induced apoptosis in cancer cells.
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