Enantiomer discrimination illustrated by the high resolution crystal structures of type 4 phosphodiesterase
Enantiomer discrimination illustrated by the high resolution crystal structures of type 4 phosphodiesterase
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DOI：
10.1021/jm051273d
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发表时间：
2006-03-23
影响因子：
7.3
通讯作者：
Ke, HM
中科院分区：
文献类型：
--
作者：
Huai, Q;Sun, YJ;Ke, HM
4型磷酸二酯酶（PDE4）抑制剂正在成为包括哮喘和慢性阻塞性肺疾病在内的许多疾病的新治疗方法。本文用PDE4D在2.0埃分辨率下对第二代抑制剂(+)-1 （L-869298, IC50 = 0.4 nM）及其对映体(-)-1 （L-869299, IC50 = 43 nM）及其共晶结构进行了生化表征。尽管亲和性相差107倍，但两种对映体在刚性活性位点上与相同的残基相互作用。较弱的(-)-1采用不利的构象，以保持镁结合水与吡啶的n -氧化物之间的关键相互作用。这些结构支持一种抑制剂一端固定不变的谷氨酰胺，另一端固定金属袋残基的模型。该模型解释了大多数观察到的结构-活性关系和基于儿茶酚醚的抑制剂的金属离子依赖性，并有助于它们的进一步设计。
Type 4 phosphodiesterase (PDE4) inhibitors are emerging as new treatments for a number of disorders including asthma and chronic obstructive pulmonary disease. Here we report the biochemical characterization on the second generation inhibitor (+)-1 (L-869298, IC50 = 0.4 nM) and its enantiomer (-)-1 (L-869299, IC50 = 43 nM) and their cocrystal structures with PDE4D at 2.0 angstrom resolution. Despite the 107-fold affinity difference, both enantiomers interact with the same sets of residues in the rigid active site. The weaker (-)-1 adopts an unfavorable conformation to preserve the pivotal interactions between the Mg-bound waters and the N-oxide of pyridine. These structures support a model in which inhibitors are anchored by the invariant glutamine at one end and the metal-pocket residues at another end. This model provides explanations for most of the observed structure-activity relationship and the metal ion dependency of the catechol-ether based inhibitors and should facilitate their further design.