Structural basis for the activity of drugs that inhibit phosphodiesterases
Structural basis for the activity of drugs that inhibit phosphodiesterases
复制标题
DOI：
10.1016/j.str.2004.10.004
复制
发表时间：
2004-12-01
期刊：
影响因子：
5.7
通讯作者：
Zhang, KYJ
中科院分区：
文献类型：
--
作者：
Card, GL;England, BP;Zhang, KYJ
磷酸二酯酶（PDEs）包括一个大家族的酶，催化水解cAMP或cGMP，并涉及多种疾病。我们描述了PDE4B， PDE4D和PDE5A的高分辨率晶体结构与十种不同的抑制剂，包括候选药物西罗米司特和罗氟司特，呼吸系统疾病的催化区域。这些共晶结构揭示了抑制剂与PDEs结合的共同方案：(i)由高度保守的疏水残基在活性位点夹心抑制剂形成的疏水钳；（ii）与控制抑制剂结合方向的不变谷氨酰胺形成氢键。基于这两种类型的保守相互作用的形成，可以很容易地识别出任何给定抑制剂的支架。这些结构上的见解将有助于设计具有更好结合亲和力的同型选择性抑制剂，并有助于发现更有效和选择性的PDE抑制剂，用于治疗各种疾病。
Phosphodiesterases (PDEs) comprise a large family of enzymes that catalyze the hydrolysis of cAMP or cGMP and are implicated in various diseases. We describe the high-resolution crystal structures of the catalytic domains of PDE4B, PDE4D, and PDE5A with ten different inhibitors, including the drug candidates cilomilast and roflumilast, for respiratory diseases. These cocrystal structures reveal a common scheme of inhibitor binding to the PDEs: (i) a hydrophobic clamp formed by highly conserved hydrophobic residues that sandwich the inhibitor in the active site; (ii) hydrogen bonding to an invariant glutamine that controls the orientation of inhibitor binding. A scaffold can be readily identified for any given inhibitor based on the formation of these two types of conserved interactions. These structural insights will enable the design of isoform-selective inhibitors with improved binding affinity and should facilitate the discovery of more potent and selective PDE inhibitors for the treatment of a variety of diseases.