Subbotina Anna, Ravna Aina W, Lysaa Roy A, Abagyan Ruben, Bugno Ryszard, Sager Georg
Experimental and Clinical Pharmacology, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø - The Arctic University of Norway, Tromsø, Norway.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California - San Diego, La Jolla, CA, USA.
J Pharm Pharmacol. 2017 Jun;69(6):675-683. doi: 10.1111/jphp.12693. Epub 2017 Feb 17.
To determine the ability of 11 sildenafil analogues to discriminate between cyclic nucleotide phosphodiesterases (cnPDEs) and to characterise their inhibitory potencies (K values) of PDE5A1-dependent guanosine cyclic monophosphate (cGMP) hydrolysis.
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 nm) and high concentration (10 μm). Complete IC plots for all analogues were performed for PDE5A-dependent cGMP hydrolysis. Docking studies and scoring were made using the ICM molecular modelling software.
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 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.
Sildenafil analogues that inhibit cellular cGMP efflux are potent inhibitors of PDE5A and PDE6C.
确定11种西地那非类似物区分环核苷酸磷酸二酯酶（cnPDEs）的能力，并表征它们对PDE5A1依赖性鸟苷环磷酸（cGMP）水解的抑制效力（K值）。
通过虚拟配体筛选（VLS）鉴定西地那非类似物，并筛选它们在低浓度（1 nM）和高浓度（10 μM）下抑制PDE1A1、PDE1B1、PDE2A1、PDE3A、PDE10A1和PDE10A2对腺苷环磷酸（cAMP）水解以及PDE5A、PDE6C、PDE9A2对cGMP水解的能力。对所有类似物进行PDE5A依赖性cGMP水解的完整IC曲线分析。使用ICM分子建模软件进行对接研究和评分。
低浓度下类似物对PDE1A1、PDE1B1、PDE2A1、PDE3A、PDE10A1和PDE10A2无抑制作用或抑制作用较弱。相比之下，低浓度下类似物对PDE5A和PDE6C的抑制作用明显且程度相似，而对PDE9A2的抑制作用则小得多。类似物对PDE5A抑制的K值范围相对较窄（1.2 - 14 nM）。西地那非分子对接在与西地那非共结晶的PDE5A1结构中。所有类似物与西地那非具有相似的结合构象。
抑制细胞cGMP外流的西地那非类似物是PDE5A和PDE6C的有效抑制剂。
