选择性pde3抑制的结构基础:对接研究

P. Fossa, F. Giordanetto, G. Menozzi, L. Mosti
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引用次数: 11

摘要

环核苷酸磷酸二酯酶(PDEs)催化第二信使腺苷-3',5'-环磷酸cAMP和cGMP的水解。至少有11种不同的PDE类型被描述:每一种类型都有一些亚型和剪接变体。PDE类型在氨基酸序列、底物特异性、抑制剂敏感性以及器官、组织和亚细胞分布方面存在差异。最近发现的PDE4B的x射线结构以及PDE3A的定点诱变实验的结果,促使我们进一步研究导致PDE3有效抑制的分子机制,作为我们之前对PDE家族酶催化位点表征的研究的继续。在现有实验数据的基础上,采用同源建模技术建立了PDE3A催化位点的理论模型。在这个模型上,进行了与强效和选择性PDE3抑制剂的深入对接研究。衍生的抑制模型个性化了有效抑制PDE3的结构要求,现在可以用于合理的药物设计目的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Structural basis for selective PDE 3 inhibition: a docking study
Cyclic nucleotide phosphodiesterases (PDEs) catalyse the hydrolysis of the second messengers adenosine-3',5'-cyclic phosphate cAMP and cGMP. At least 11 different PDE types have been described: each of these groups a number of subtypes and splice variants. The PDE types differ in their amino acid sequence, substrate specificity, inhibitor sensitivity and in their organ, tissue and subcellular distribution. The recently solved X-ray structure of PDE4B as well as the results of site-directed mutagenesis experiments on PDE3A, prompted us to further investigate into the molecular mechanism that leads to effective PDE3 inhibition, as a prosecution of our previous studies on characterisation of the catalytic site of PDE family enzymes. On the basis of the experimental data available, a theoretical model of the catalytic site of PDE3A employing homology-modelling techniques was built. On this model thorough docking studies with potent and selective PDE3 inhibitors were performed. The derived inhibition model individuated structural requirements for potent PDE3 inhibition and can now be exploited for rational drug design purposes.
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