Insight into binding of phosphodiesterase-9A selective inhibitors by crystal structures and mutagenesis.
Insight into binding of phosphodiesterase-9A selective inhibitors by crystal structures and mutagenesis.
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DOI：
10.1021/jm901519f
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发表时间：
2010-02-25
影响因子：
7.3
通讯作者：
Ke H
中科院分区：
文献类型：
--
作者：
Wang H;Luo X;Ye M;Hou J;Robinson H;Ke H
PDE9 抑制剂已被研究作为治疗心血管疾病、糖尿病和神经退行性疾病的药物。为了说明抑制剂的选择性，PDE9A 催化结构域与 PDE9 抑制剂对映体复合的晶体结构 1-(2-氯苯基)-6-(3,3,3-三氟-2-甲基丙基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-one 测定((R)-BAY73-6691或(S)-BAY73-6691，1r或1s)并进行诱变。结构表明1r和1s的氟甲基具有不同的方向，而抑制剂的其他部分通常与PDE9A相互作用。这些差异可以解释 1r (IC50 = 22 nM) 和 1s (IC50 = 88 nM) 的亲和力略有不同。诱变实验表明，结合残基对抑制剂敏感性的贡献差异很大，从几倍到三个数量级。在晶体结构的基础上，对模拟最近发表的 PDE9 抑制剂的假设化合物进行了建模，以深入了解抑制剂的选择性。
PDE9 inhibitors have been studied as therapeutics for treatment of cardiovascular diseases, diabetes, and neurodegenerative disorders. To illustrate the inhibitor selectivity, the crystal structures of the PDE9A catalytic domain in complex with the enantiomers of PDE9 inhibitor 1-(2-chlorophenyl)-6-(3,3,3-trifluoro-2-methylpropyl)-1H-pyrazolo[3,4-d]pyrimidine-4(5H)-one ((R)-BAY73-6691 or (S)-BAY73-6691, 1r or 1s) were determined and mutagenesis was performed. The structures showed that the fluoromethyl groups of 1r and 1s had different orientations while the other parts of the inhibitors commonly interacted with PDE9A. These differences may explain the slightly different affinity of 1r (IC50 = 22 nM) and 1s (IC50 = 88 nM). The mutagenesis experiments revealed that contribution of the binding residues to the inhibitor sensitivity varies dramatically, from a few of folds to three orders of magnitude. On the basis of the crystal structures, a hypothesized compound that simulates the recently published PDE9 inhibitors was modeled to provide insight into the inhibitor selectivity.
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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：
4.1
作者：
Diederen, R. M. H.;La Heij, E. C.;de Vente, J.
通讯作者：
de Vente, J.
影响因子：
2.9
作者：
Huai, Q;Colicelli, J;Ke, HM
通讯作者：
Ke, HM
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.