Laboratory of Computational and Systems Biology, School of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan, ROC.
J Biomol Struct Dyn. 2010 Apr;27(5):627-40. doi: 10.1080/07391102.2010.10508577.
Erectile dysfunction (ED) is a sexual disorder mainly caused by decrease in cellular concentration of cyclic guanosine monophosphate (cGMP), which is degraded by phosphodiesterase type-5 (PDE-5). As a potent therapeutic target, inhibitors such as Viagra , Cialis, and Levitra have already been developed to target PDE-5 for treating ED; traditional Chinese medicine, Epimedium sagittatum, also has shown prominent results as well. To developed new PDE-5 inhibitors, we performed a virtual screening of traditional Chinese medicine (TCM) database and docking analyses to identify candidates. Known PDE-5 inhibitors were used to construct a three dimensional quantitative structure-activity relationship (3D QSAR) model by HypoGen program. From docking analyses, isochlorogenic acid b was identified as the most potential inhibitory compound. De novo evolution designed 47 derivatives. Of the 47 derivatives, seven were able to map into the pharmacophore model, and these seven compounds were suggested to be the most promising leads for inhibiting PDE-5. An analysis of the hydrogen bond interactions formed between the docked ligands and PDE-5 identified ASN662, SER663 and GLN817 as the most frequently interacting residues. A total of eight novel leading compounds were identified to have favorable interaction with PDE-5. These compounds all had hydrogen bond interactions with three key residues that could be further investigated for understanding of PDE-5 and ligands interaction.
勃起功能障碍（ED）主要是由细胞中环鸟苷酸（cGMP）浓度降低引起的，cGMP 被磷酸二酯酶 5（PDE-5）降解。作为一个有效的治疗靶点，已经开发出了许多抑制剂，如伟哥、希爱力和利维坦，以针对 PDE-5 治疗 ED；而中药淫羊藿也显示出了显著的效果。为了开发新的 PDE-5 抑制剂，我们对中药（TCM）数据库进行了虚拟筛选和对接分析，以确定候选药物。已知的 PDE-5 抑制剂被用来通过 HypoGen 程序构建三维定量构效关系（3D QSAR）模型。通过对接分析，鉴定出绿原酸 b 是最有潜力的抑制化合物。从头设计了 47 个衍生物。在 47 个衍生物中，有 7 个能够映射到药效基团模型中，这 7 个化合物被认为是抑制 PDE-5 的最有前途的先导化合物。对接配体与 PDE-5 之间形成的氢键相互作用分析表明，ASN662、SER663 和 GLN817 是最常相互作用的残基。总共鉴定出 8 种新型先导化合物与 PDE-5 具有良好的相互作用。这些化合物都与三个关键残基有氢键相互作用，可以进一步研究它们与 PDE-5 及其配体相互作用的机制。
