Virtual Screening and Drug Design for PDE-5 Receptor from Traditional Chinese Medicine Database
Virtual Screening and Drug Design for PDE-5 Receptor from Traditional Chinese Medicine Database
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DOI：
10.1080/07391102.2010.10508577
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发表时间：
2010-04-01
影响因子：
4.4
通讯作者：
Chen, Calvin Yu-Chian
中科院分区：
文献类型：
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作者：
Chen, Calvin Yu-Chian
勃起功能障碍（ED）是一种主要由细胞内环磷酸鸟苷（cGMP）浓度降低引起的性功能障碍，cGMP被5型磷酸二酯酶（PDE-5）降解。作为有效的治疗靶点，伟哥 (R)、西力士 (R) 和艾力达 (R) 等抑制剂已被开发用于靶向 PDE-5 来治疗 ED；传统中药，箭叶淫羊藿。也取得了显著成果。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并进行对接分析来确定候选药物。 HypoGen 程序使用已知的 PDE-5 抑制剂构建三维定量构效关系 (3D QSAR) 模型。根据对接分析，异绿原酸 b 被确定为最有潜力的抑制化合物。 De novo Evolution设计了47种衍生品。在 47 种衍生物中，有 7 种能够映射到药效团模型中。这七种化合物被认为是最有希望抑制 PDE-5 的先导化合物。对对接配体和 PDE-5 之间形成的氢键相互作用的分析确定 ASN662、SER663 和 GLN817 是最频繁相互作用的残基。总共有 8 种新型先导化合物被鉴定出与 PDE-5 具有良好的相互作用。这些化合物均与三个关键残基具有氢键相互作用，可以进一步研究这些残基以了解 PDE-5 和配体相互作用。
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 (R), Cialis (R), and Levitra (R) 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.