• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>The Internet Journal of Pharmacology >The Identification of De-Alkylation Reactions Catalysed by Cytochrome P450 using Pharmacophore Three-dimensional Structure
【24h】

The Identification of De-Alkylation Reactions Catalysed by Cytochrome P450 using Pharmacophore Three-dimensional Structure

机译：药理学三维结构鉴定细胞色素P450催化的脱烷基反应

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Quantitative structure activity relationships (QSAR) and pharmacophore three-dimensional structure modelling provide possible methods for understanding the first pass metabolism of human cytochrome P450 substrates in the absence of reliable crystal structures of the human enzymes. The increasing need for alternative and objective methods of metabolism prediction has developed into computational approaches to the problem of understanding the enzyme and substrate behaviour. By analysis of the three-dimensional structure known to be catalysed by human P450 and comparison to other substrates involved in similar alkyl removal reactions, along with the alignment of molecular interaction potentials (MIP), a common template for specific de-alkylations is proposed. Introduction Cytochrome P450 is not specifically one entity, but a widely populated family of haem-thiolate enzyme proteins capable of redox (mono-oxygenase) behaviour (G. Smith, M. J. Stubbins, L. W. Harries, 2004). Human P450s are known to remove drugs from the patient efficiently by “first pass metabolism” in the liver (Rang and Dale, 1987; Gibson and Skett 2001).The prediction of the metabolism and specificity of substrates is a difficult yet important task for xenobiotics (Marechal, Sutcliffe, 2006). Various attempts have been made into categorizing reactions according to the active cytochrome engaged in the investigation (Etkins et al. 2001) as well as QSAR (quantitative structure activity relationship) investigations in previous work. Although the number of members per dataset are small, these were limited by the available information through literature (Lewis et al. 2002-2004). For example, the structures displayed in figure 1 appear to show no direct common structural trends with each other, apart from the necessary group for the selected oxygen de-ethylation reaction to occur by P450. By taking the approach of how the cytochrome might “see” the substrates for reception then areas of biological similarity become apparent. This particular area of predictive research is still well within its infancy since the crystal data for human cytochromes with bound ligands are rare and usually of poor resolution. In an attempt to develop the situation, mathematical approaches to metabolism have been growing in popularity since the 1970's (Hansch 1972). Recent research has suggested that Molecular interaction potentials (MIP) may play an important role in the comparisons of several structures for SAR (structure activity relationships) and Quantitative SAR (QSAR)(Rodrigo et al. 2002). By computationally generating MIP, the interaction “probes” of a structure, and thus their interacting properties can be directly compared to other members undergoing a similar reaction or those which are related by catalyst. The most important probe to consider is the Electrostatic Potential (ESP) of a structure. One such program is MOE (Chemical Computing Group Inc.) which generates ESP grids and displays the ESP map by application of the Poisson-Boltzmann Equation (PBE) to the prediction of electrostatically preferred locations of hydrophobic, H-bond acceptor and H-bond donor locations. Comparing two structures from the oxygen de-ethylation dataset in Figures 2 and 3, the structures were first minimised within MOE using the AM1 UHF method, then the ESP map was generated at a –2 kcal/mol contour level. It can be seen that there are areas of attractive ESP within the centres of the aromatic rings in both of the substrates, approximately 2.8? from the site of reaction, and another ESP site located at a distance of approximately 6.5? with both sites being located in the plane defined by the aromatic ring system. The precise magnitudes of the ESP points are not critical at this stage of the investigation. With more computational cost, the substrates could be superimposed to further enforce the positions of the ESP points and display the alignment of such “template” points. Also to be taken into conside
机译：定量结构活性关系（QSAR）和药效团三维结构建模为了解人细胞色素P450底物在没有可靠酶结构的情况下的首过代谢提供了可能的方法。对新陈代谢预测的替代和客观方法的需求日益增长，已发展成为解决了解酶和底物行为问题的计算方法。通过分析已知由人P450催化的三维结构，并与参与类似烷基去除反应的其他底物进行比较，并与分子相互作用电势（MIP）进行比对，提出了用于特定脱烷基反应的通用模板。简介细胞色素P450并不是一个具体的实体，而是一个广泛的血红素硫醚酶蛋白家族，能够氧化还原（单加氧酶）行为（G. Smith，M. J. Stubbins，L. W. Harries，2004）。已知人类P450可以通过肝脏中的“首过代谢”有效地从患者体内去除药物（Rang和Dale，1987; Gibson和Skett，2001）。对异源物质的代谢和特异性的预测是一项困难而重要的任务（Marechal，Sutcliffe，2006年）。根据参与研究的活性细胞色素（Etkins等，2001）以及先前工作中的QSAR（定量结构活性关系）研究，已经做出了各种反应分类的尝试。尽管每个数据集的成员数量很少，但是这些都受到文献中可用信息的限制（Lewis等人2002-2004）。例如，图1中显示的结构似乎彼此之间没有显示出直接的共同结构趋势，除了通过P450进行所选的氧脱乙基反应所需的基团。通过采取细胞色素如何“看到”接收基质的方法，生物学相似性区域变得显而易见。由于具有结合的配体的人细胞色素的晶体数据很少，而且通常分辨率较差，因此该预测研究的特定领域仍处于起步阶段。为了发展这种状况，自1970年代以来，新陈代谢的数学方法已经越来越流行（Hansch 1972）。最近的研究表明，分子相互作用潜能（MIP）在SAR的几种结构（结构活性关系）和定量SAR（QSAR）的比较中可能起重要作用（Rodrigo等，2002）。通过计算生成MIP，可以将结构的相互作用“探针”及其相互作用特性直接与进行相似反应或与催化剂相关的其他成员进行比较。要考虑的最重要的探针是结构的静电势（ESP）。 MOE（化学计算集团公司）就是这样一种程序，该程序生成ESP网格并通过应用Poisson-Boltzmann方程（PBE）预测疏水性，H键受体和H键的静电优先位置来显示ESP图。供体位置。比较图2和图3中的氧脱乙基数据集的两种结构，首先使用AM1 UHF方法在MOE中最小化这些结构，然后以–2 kcal / mol的轮廓水平生成ESP图。可以看出，在两个衬底的芳环的中心都存在有吸引力的ESP区域，大约为2.8Ω。从反应位点开始，另一个ESP位点距离大约6.5？两个位点都位于芳香环系统定义的平面上。在调查的这个阶段，ESP点的精确大小并不重要。随着更多的计算成本，可以叠加基板以进一步加强ESP点的位置并显示此类“模板”点的对齐方式。也要考虑

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号