Abstract
ObjectivesTo determine the ability of 11 sildenafil analogues to discriminate between cyclic nucleotide phosphodiesterases (cnPDEs) and to characterise their inhibitory potencies (K i values) of PDE5A1‐dependent guanosine cyclic monophosphate (cGMP) hydrolysis.MethodsSildenafil 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 nm) and high concentration (10 μm). Complete IC 50 plots for all analogues were performed for PDE5A‐dependent cGMP hydrolysis. Docking studies and scoring were made using the ICM molecular modelling software.Key findingsThe 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 i values for PDE5A inhibition (1.2–14 nm). The sildenafil molecule was docked in the structure of PDE5A1 co‐crystallised with sildenafil. All the analogues had similar binding poses as sildenafil.ConclusionsSildenafil analogues that inhibit cellular cGMP efflux are potent inhibitors of PDE5A and PDE6C.
Highlights
Cyclic nucleotide signalling plays an essential role in normal cell physiology and is impaired in many pathological conditions, such as heart disease, pulmonary hypertension, chronic obstructive pulmonary disease, obesity, diabetes and cancer.[1]
PDE5 (Ki ratio reduction), we identified a series of 11 high-affinity cGMP transporter inhibitors by virtual ligand screening (VLS).[8]
The screening was performed by BPS Bioscience Inc. (San Diego, CA, USA) with the following materials: PDE assay buffer (BPS), PDE binding agent (BPS), PDE binding agent diluent for cAMP (BPS), PDE binding agent diluent for cGMP (BPS), Bay 60-7550 was purchased from Cayman Chemicals (Ann Arbor, MI, USA), and cilostamide, sildenafil citrate and papaverine were purchased from Axxora (San Diego, CA, USA)
Summary
Cyclic nucleotide signalling plays an essential role in normal cell physiology and is impaired in many pathological conditions, such as heart disease, pulmonary hypertension, chronic obstructive pulmonary disease, obesity, diabetes and cancer.[1] The family of human phosphodiesterases (PDEs) comprises 11 main forms, from which PDEs 4, 7 and 8 are adenosine cyclic monophosphate (cAMP) selective; PDEs 5, 6 and 9 are guanosine cyclic monophosphate (cGMP) selective; and PDEs 1, 2, 3, 10 and 11 hydrolyse both cAMP and cGMP.[2] sildenafil raises cellular cGMP levels by two mechanisms, reduction in cellular efflux by ATP-binding cassette transporter subfamily C, member 5 (ABCC5), previously termed multidrug resistance-associated protein 5 (MRP5),[3] in addition to inhibition of PDE5 activity.[4]. Non-selective PDE inhibitors, such as IBMX (3-isobutyl-1-methyl-xanthine),[6,7] caffeine and theophylline,[6]
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