Structure-based discovery of highly selective phosphodiesterase-9A inhibitors and implications for inhibitor design.
Structure-based discovery of highly selective phosphodiesterase-9A inhibitors and implications for inhibitor design.
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DOI：
10.1021/jm301189c
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发表时间：
2012-10-11
影响因子：
7.3
通讯作者：
Ke, Hengming
中科院分区：
文献类型：
--
作者：
Meng, Fei;Hou, Jing;Shao, Yong-Xian;Wu, Pei-Ying;Huang, Manna;Zhu, Xinhai;Cai, Yonghong;Li, Zhe;Xu, Jie;Liu, Peiqing;Luo, Hai-Bin;Wan, Yiqian;Ke, Hengming
通过基于结构的设计和计算对接的结合，发现了一系列新的磷酸二酯酶-9(PDE9)抑制剂，其中含有6-氨基吡唑嘧啶酮的支架。该方法大大节省了化学合成的工作量，是一种有效的发现抑制剂的方法。最好的化合物28对PDE9和PDE5的IC50分别为21 nm和3.3µM，与其他PDE系列相比，选择性约为三个数量级。测定了28与PDE9催化结构域的晶体结构，发现28与Tyr424之间存在氢键。这种氢键可能解释了28对PDE1B的860倍的选择性，而BAY73-6691的大约30倍的选择性。因此，我们的研究表明，Tyr424是PDE8和PDE9的独特残基，是提高PDE9抑制剂选择性的潜在靶点。
A new series of phosphodiesterase-9 (PDE9) inhibitors that contain a scaffold of 6-amino-pyrazolopyrimidinone have been discovered by a combination of structure-based design and computational docking. This procedure significantly saved load of chemical synthesis and is an effective method for the discovery of inhibitors. The best compound 28 has an IC50 of 21 nM and 3.3 µM respectively for PDE9 and PDE5, and about three orders of magnitude of selectivity against other PDE families. The crystal structure of the PDE9 catalytic domain in complex with 28 has been determined and shows a hydrogen bond between 28 and Tyr424. This hydrogen bond may account for the 860-fold selectivity of 28 against PDE1B, in comparison with about 30-fold selectivity of BAY73-6691. Thus, our studies suggest that Tyr424, a unique residue of PDE8 and PDE9, is a potential target for improvement of selectivity of PDE9 inhibitors.
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DOI：
10.1126/science.1152506
发表时间：
2008-05-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
O'Neill JS;Maywood ES;Chesham JE;Takahashi JS;Hastings MH
通讯作者：
Hastings MH
影响因子：
158.5
作者：
Galiè, N;Ghofrani, HA;Simonneau, G
通讯作者：
Simonneau, G
影响因子：
4.7
作者：
Hutson, P. H.;Finger, E. N.;Parmentier-Batteur, S.
通讯作者：
Parmentier-Batteur, S.
影响因子：
2.7
作者：
DeNinno, Michael P.;Andrews, Melissa;Gibbs, E. Michael
通讯作者：
Gibbs, E. Michael
DOI：
10.1073/pnas.0708850105
发表时间：
2008-09-09
影响因子：
11.1
作者：
Liu, Shenping;Mansour, Mahmoud N.;Menniti, Frank S.
通讯作者：
Menniti, Frank S.