Phosphodiesterase Inhibitors: Factors That Influence Potency, Selectivity, and Action
Phosphodiesterase Inhibitors: Factors That Influence Potency, Selectivity, and Action
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DOI：
10.1007/978-3-642-17969-3_2
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发表时间：
2011-01-01
期刊：
影响因子：
--
通讯作者：
Conti, Marco
中科院分区：
文献类型：
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作者：
Francis, Sharron H.;Houslay, Miles D.;Conti, Marco
环核苷酸磷酸二酯酶（PDEs）是有希望的药物干预靶点。多个PDE基因的存在，每个基因产生的同种异构体的多样性，同种异构体的选择性组织和细胞表达，细胞内的区隔以及PDE蛋白的一系列构象是针对这些酶的药物开发的一些挑战。尽管如此，pde的许多特性也被视为在为某些治疗适应症设计新化合物时增加特异性和选择性的独特机会。本章概述了与PDE抑制剂的设计和使用相关的主要概念。根据最新的x射线晶体结构，总结了PDEs的催化结构和构象的总体结构和性质。讨论了不同家族催化结构域的独特性质，以及探测PDE性质及其与小分子相互作用的技术挑战。翻译后修饰和蛋白-蛋白相互作用的影响是设计PDE抑制剂时需要考虑的额外因素。PDE抑制剂与其他蛋白质的相互作用也需要考虑和讨论。
Cyclic nucleotide phosphodiesterases (PDEs) are promising targets for pharmacological intervention. The presence of multiple PDE genes, diversity of the isoforms produced from each gene, selective tissue and cellular expression of the isoforms, compartmentation within cells, and an array of conformations of PDE proteins are some of the properties that challenge the development of drugs that target these enzymes. Nevertheless, many of the characteristics of PDEs are also viewed as unique opportunities to increase specificity and selectivity when designing novel compounds for certain therapeutic indications. This chapter provides a summary of the major concepts related to the design and use of PDE inhibitors. The overall structure and properties of the catalytic domain and conformations of PDEs are summarized in light of the most recent X-ray crystal structures. The distinctive properties of catalytic domains of different families as well as the technical challenges associated with probing PDE properties and their interactions with small molecules are discussed. The effect of posttranslational modifications and protein-protein interactions are additional factors to be considered when designing PDE inhibitors. PDE inhibitor interaction with other proteins needs to be taken into account and is also discussed.