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Inhibition of PDE5A1 guanosine cyclic monophosphate ( cGMP) hydrolysing activity by sildenafil analogues that inhibit cellular cGMP efflux.
- Source :
- Journal of Pharmacy & Pharmacology; Jun2017, Vol. 69 Issue 6, p675-683, 9p
- Publication Year :
- 2017
-
Abstract
- Objectives To determine the ability of 11 sildenafil analogues to discriminate between cyclic nucleotide phosphodiesterases (cn PDEs) and to characterise their inhibitory potencies ( K<subscript>i</subscript> values) of PDE5A1-dependent guanosine cyclic monophosphate ( cGMP) hydrolysis. Methods Sildenafil analogues were identified by virtual ligand screening ( VLS) and screened for their ability to inhibit adenosine cyclic monophosphate ( cAMP) hydrolysis by PDE1A1, PDE1B1, PDE2A1, PDE3A, PDE10A1 and PDE10A2, and cGMP hydrolysis by PDE5A, PDE6C, PDE9A2 for a low (1 n m) and high concentration (10 μ m). Complete IC<subscript>50</subscript> plots for all analogues were performed for PDE5A-dependent cGMP hydrolysis. Docking studies and scoring were made using the ICM molecular modelling software. Key findings The analogues in a low concentration showed no or low inhibition of PDE1A1, PDE1B1, PDE2A1, PDE3A, PDE10A1 and PDE10A2. In contrast, PDE5A and PDE6C were markedly inhibited to a similar extent by the analogues in a low concentration, whereas PDE9A2 was much less inhibited. The analogues showed a relative narrow range of K<subscript>i</subscript> values for PDE5A inhibition (1.2-14 n m). The sildenafil molecule was docked in the structure of PDE5A1 co-crystallised with sildenafil. All the analogues had similar binding poses as sildenafil. Conclusions Sildenafil analogues that inhibit cellular cGMP efflux are potent inhibitors of PDE5A and PDE6C. [ABSTRACT FROM AUTHOR]
- Subjects :
- GUANOSINE
HYDROLYSIS
NUCLEOTIDES
SILDENAFIL
LIGANDS (Biochemistry)
Subjects
Details
- Language :
- English
- ISSN :
- 00223573
- Volume :
- 69
- Issue :
- 6
- Database :
- Complementary Index
- Journal :
- Journal of Pharmacy & Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 122859780
- Full Text :
- https://doi.org/10.1111/jphp.12693