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dc.contributor.authorKashgari, Farzane Kuresh
dc.contributor.authorRavna, Aina Westrheim
dc.contributor.authorSager, Georg
dc.contributor.authorLyså, Roy Andre
dc.contributor.authorEnyedy, Istvan
dc.contributor.authorDietrichs, Erik Sveberg
dc.date.accessioned2021-03-10T07:49:08Z
dc.date.available2021-03-10T07:49:08Z
dc.date.issued2020-03-28
dc.description.abstract<i>Background</i> - Clinical studies have reported overexpression of PDE5 and elevation of intracellular cyclic GMP in various types of cancer cells. ABCC5 transports cGMP out of the cells with high affinity. PDE5 inhibitors prevent both cellular metabolism and cGMP efflux by inhibiting ABCC5 as well as PDE5. Increasing intracellular cGMP is hypothesized to promote apoptosis and growth restriction in tumor cells and also has potential for clinical use in treatment of cardiovascular disease and erectile dysfunction. Vardenafil is a potent inhibitor of both PDE5 and ABCC5-mediated cGMP cellular efflux. Nineteen novel vardenafil analogs that have been predicted as potent inhibitors by VLS were chosen for tests of their ability to inhibit ATP- dependent transport of cGMP by measuring the accumulation of cyclic GMP in inside-out vesicles.<br><br> <i>Aim</i> - In this study, we investigated the ability of nineteen new compounds to inhibit ABCC5- mediated cGMP transport. We also determined the Ki values of the six most potent compounds.<br><br> <i>Methods</i> - Preparation of human erythrocyte inside out vesicles and transport assay.<br><br> <i>Results</i> - Ki values for six of nineteen compounds that showed more than 50 % inhibition of cGMP transport in the screening test were determined and ranged from 1.1 to 23.1 μM. One compound was significantly more potent than the positive control, sildenafil.<br><br> <i>Conclusion</i> - Our findings show that computational screening correctly identified vardenafil-analogues that potently inhibit cGMP efflux-pumps from cytosol and could have substantial clinical potential in treatment of patients with diverse disorders.en_US
dc.identifier.citationKashgari, Ravna aw, Sager gs, Lyså RA, Enyedy I, Dietrichs ES. Identification and experimental confirmation of novel cGMP efflux inhibitors by virtual ligand screening of vardenafil-analogues. Biomedicine and Pharmacotherapy. 2020;126:110109:1-8en_US
dc.identifier.cristinIDFRIDAID 1804391
dc.identifier.doi10.1016/j.biopha.2020.110109
dc.identifier.issn0753-3322
dc.identifier.issn1950-6007
dc.identifier.urihttps://hdl.handle.net/10037/20662
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.relation.journalBiomedicine and Pharmacotherapy
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2020 The Author(s)en_US
dc.subjectVDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710en_US
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710en_US
dc.titleIdentification and experimental confirmation of novel cGMP efflux inhibitors by virtual ligand screening of vardenafil-analoguesen_US
dc.type.versionpublishedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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