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首页> 外文期刊>Journal of Medicinal Chemistry >Three Dimensional Pharmacophore Modeling of Human CYP17 Inhibitors. Potential Agents for Prostate Cancer Therapy
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Three Dimensional Pharmacophore Modeling of Human CYP17 Inhibitors. Potential Agents for Prostate Cancer Therapy

机译：人CYP17抑制剂的三维药理学建模。前列腺癌治疗的潜在药物

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摘要

We report here a molecular modeling investigation of steroidal and nonsteroidal inhibitors of human cytochrome P450 17α-hydroxylase-17,20-lyase (CYP17). Using the pharmacophore perception technique, we have generated common-feature pharmacophore model(s) to explain the putative binding requirements for two classes of human CYP17 inhibitors. Common chemical features in the steroid and nonsteroid human CYP17 enzyme inhibitors, as deduced by the Catalyst/HipHop program, are one to two hydrogen bond acceptors (HBAs) and three hydrophobic groups. For azole-steroidal ligands, the 3β-OH group of ring A and the N-3 of the azole ring attached to ring D at C-17 act as hydrogen bond acceptors. A model that permits hydrogen bond interaction between the azole functionality on ring D and the enzyme is consistent with experimental deductions for type II CYP17 inhibitors where a sixth ligating atom interacts with Fe(II) of heme. In general, pharmacophore models derived for steroid and nonsteroidal compounds bear striking similarities to all azole sites mapping the HBA functionality and to three hydrophobic features describing the hydrophobic interactions between the ligands and the enzyme. Using the pharmacophore model derived for azole-steroidal inhibitors as a 3D search query against several 3D multiconformational Catalyst formatted databases, we identified several steroidal compounds with potential inhibition of this enzyme. Biological testing of some of these compounds show low to high inhibitory potency against the human CYP17 enzyme. This shows the potential of our pharmacophore model in identifying new and potent CYP17 inhibitors. Further refinement of the model is in progress with a view to identifying and optimizing new leads.
机译：我们在这里报告了人类细胞色素P45017α-羟化酶-17,20-裂解酶（CYP17）的甾体和非甾体抑制剂的分子模型研究。使用药效基团感知技术，我们生成了通用功能的药效基团模型来解释两类人CYP17抑制剂的假定结合要求。由Catalyst / HipHop程序推论，类固醇和非类固醇人CYP17酶抑制剂的常见化学特征是一到两个氢键受体（HBA）和三个疏水基团。对于唑-甾族配体，环A的3β-OH基团和在C-17处连接至环D的唑环的N-3充当氢键受体。允许D环上的唑官能团与酶之间发生氢键相互作用的模型与II型CYP17抑制剂的实验推论一致，其中第六个连接原子与血红素的Fe（II）相互作用。通常，衍生为类固醇和非类固醇化合物的药效团模型与映射HBA功能的所有唑位点和描述配体与酶之间的疏水相互作用的三个疏水性特征具有惊人的相似性。使用针对几个甾族3D多构象催化剂格式数据库进行3D搜索查询而获得的唑类固醇抑制剂的药效团模型，我们确定了几种对该酶具有潜在抑制作用的甾族化合物。其中一些化合物的生物学测试显示，其对人CYP17酶的抑制能力低至高。这显示了我们的药效团模型在鉴定新的和有效的CYP17抑制剂中的潜力。为了识别和优化新的潜在客户，正在进一步完善模型。

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