Discovery of 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno [2,3-c]pyrrol-9(2H)-one as a phosphodiesterase-5 inhibitor and its complex crystal structure
Discovery of 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno [2,3-c]pyrrol-9(2H)-one as a phosphodiesterase-5 inhibitor and its complex crystal structure
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发现 3-(4-羟基苄基)-1-(噻吩-2-基)苯并[2,3-c]吡咯-9(2H)-酮作为磷酸二酯酶 5 抑制剂及其复杂的晶体结构
DOI：
10.1016/j.bcp.2014.02.013
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发表时间：
2014-05-01
影响因子：
5.8
通讯作者：
Luo, Hai-Bin
中科院分区：
文献类型：
--
作者：
Shang, Na-Na;Shao, Yong-Xian;Luo, Hai-Bin
磷酸二酯酶-5（PDE5）抑制剂已被批准用于治疗勃起功能障碍和肺动脉高压，但对发现PDE5抑制剂的热情仍在继续，因为它们具有潜在的新应用。本文报道了通过结构设计、分子对接、化学合成和酶学性质鉴定发现的一系列新的PDE5抑制剂。最好的化合物3（4-羟基苄基）-1-（噻吩-2-基）色烯并[2，3-c]吡咯-9（2H）-酮（57）对PDE 5催化结构域的IC 50为17 nM，并且对其他PDE家族具有良好的选择性。在2埃分辨率下测定与57复合的PDE 5催化结构域的晶体结构，并显示57占据与其他PDE 5抑制剂相同的口袋，但在细节上具有不同的结合模式。基于57的结合模式，可以提出一种新的支架作为PDE抑制剂的候选物。(C)2014爱思唯尔公司All rights reserved.
Phosphodiesterase-5 (PDE5) inhibitors have been approved for the treatment of erectile dysfunction and pulmonary hypertension, but enthusiasm on discovery of PDE5 inhibitors continues for their potential new applications. Reported here is discovery of a series of new PDE5 inhibitors by structure-based design, molecular docking, chemical synthesis, and enzymatic characterization. The best compound, 3(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one (57), has an IC50 of 17 nM against the PDE5 catalytic domain and good selectivity over other PDE families. The crystal structure of the PDE5 catalytic domain in complex with 57 was determined at 2 angstrom resolution and showed that 57 occupies the same pocket as other PDE5 inhibitors, but has a different binding pattern in detail. On the basis of the binding pattern of 57, a novel scaffold can be proposed as a candidate of PDE inhibitors. (C) 2014 Elsevier Inc. All rights reserved.