Sung Byung-Je, Hwang Kwang Yeon, Jeon Young Ho, Lee J I, Heo Yong-Seok, Kim Jin Hwan, Moon Jinho, Yoon Jung Min, Hyun Young-Lan, Kim Eunmi, Eum Sung Jin, Park Sam-Yong, Lee Jie-Oh, Lee Tae Gyu, Ro Seonggu, Cho Joong Myung
Division of Drug Discovery, CrystalGenomics, Inc., Daedeok Biocommunity, Jeonmin-dong, Yuseong-gu, Daejeon, 305-390, South Korea.
Nature. 2003 Sep 4;425(6953):98-102. doi: 10.1038/nature01914.
Phosphodiesterases (PDEs) are a superfamily of enzymes that degrade the intracellular second messengers cyclic AMP and cyclic GMP. As essential regulators of cyclic nucleotide signalling with diverse physiological functions, PDEs are drug targets for the treatment of various diseases, including heart failure, depression, asthma, inflammation and erectile dysfunction. Of the 12 PDE gene families, cGMP-specific PDE5 carries out the principal cGMP-hydrolysing activity in human corpus cavernosum tissue. It is well known as the target of sildenafil citrate (Viagra) and other similar drugs for the treatment of erectile dysfunction. Despite the pressing need to develop selective PDE inhibitors as therapeutic drugs, only the cAMP-specific PDE4 structures are currently available. Here we present the three-dimensional structures of the catalytic domain (residues 537-860) of human PDE5 complexed with the three drug molecules sildenafil, tadalafil (Cialis) and vardenafil (Levitra). These structures will provide opportunities to design potent and selective PDE inhibitors with improved pharmacological profiles.
磷酸二酯酶（PDEs）是一类可降解细胞内第二信使环磷酸腺苷（cAMP）和环磷酸鸟苷（cGMP）的酶超家族。作为具有多种生理功能的环核苷酸信号传导的重要调节因子，PDEs是治疗包括心力衰竭、抑郁症、哮喘、炎症和勃起功能障碍在内的各种疾病的药物靶点。在12个PDE基因家族中，cGMP特异性PDE5在人海绵体组织中发挥主要的cGMP水解活性。它是枸橼酸西地那非（伟哥）和其他类似药物治疗勃起功能障碍的靶点。尽管迫切需要开发选择性PDE抑制剂作为治疗药物，但目前只有cAMP特异性PDE4的结构可用。在此，我们展示了人PDE5催化结构域（537-860位氨基酸残基）与三种药物分子西地那非、他达拉非（希爱力）和伐地那非（艾力达）复合的三维结构。这些结构将为设计具有改善药理学特性的强效和选择性PDE抑制剂提供机会。
