Method for including the dynamic fluctuations of a protein in computer-aided drug design
Method for including the dynamic fluctuations of a protein in computer-aided drug design
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DOI：
10.1021/jp991997z
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发表时间：
1999-12-09
影响因子：
2.9
通讯作者：
McCammon, JA
中科院分区：
文献类型：
--
作者：
Carlson, HA;Masukawa, KM;McCammon, JA
我们最近提出了一种新的药效团设计方法，可以结合目标活性位点的固有灵活性。酶系统的灵活性是通过收集非复合蛋白质的许多构象来描述的：这种构象状态的集合可以来自分子动力学 (MD) 模拟、多个晶体结构或许多 NMR 结构。通过多拷贝计算确定补充活性位点的官能团的结合位点。这些计算是针对每种蛋白质构象进行的，提供了大量潜在的结合位点。每个蛋白质构象的笛卡尔坐标通过必需催化残基的 RMS 拟合进行叠加，并且药效团模型通过在许多蛋白质构象上保守的结合区域来描述。此前，我们使用 MD 模拟中蛋白质的 11 种构象开发了 HIV-1 整合酶的“动态”药效团模型； MUSIC 程序用于计算活性位点每种构型中甲醇分子的结合位置。在这里，我们提出了用来自两种新晶体结构的蛋白质的单一构象开发的“静态”药效团模型（多拷贝方法的标准方案）。在拟合已知的 HIV-1 整合酶抑制剂方面，静态模型的表现不如之前的动态模型。为了测试动态药效团方法的适用性以及任何可靠的蛋白质构象来源都适用的假设，我们现在基于也用于静态模型开发的两种晶体结构开发了第二个动态药效团模型。虽然基于两种晶体结构的动态模型不像之前的动态模型那样适合许多已知的抑制剂，但它比静态模型有了显着的改进。随着新晶体结构的出现，预计会有更好的性能。然而，值得注意的是，仅使用两种结构可以使模型得到很大的改进。
We have recently presented a new pharmacophore design method that allows for the incorporation of the inherent flexibility of a target active site. The flexibility of the enzymatic system is described by collecting many conformations of the uncomplexed protein: this ensemble of conformational states can come from a molecular dynamics (MD) simulation, multiple crystal structures, or many NMR structures. Binding sites for functional groups that complement the active site are determined throu,oh multiple-copy calculations. These calculations are conducted for each protein conformation, providing a large collection of potential binding sites. The Cartesian coordinates from each protein conformation are overlaid through RMS fitting of essential catalytic residues, and the pharmacophore model is described by binding regions that are conserved over many protein conformations. Previously, we developed a "dynamic" pharmacophore model for HIV-1 integrase using 11 conformations of the protein from an MD simulation; the MUSIC procedure was used to calculate binding positions for methanol molecules in each configuration of the active site. Here we present "static" pharmacophore models developed with a single conformation of the protein from two new crystal structures (standard protocol for multiple-copy methods). The static models do not perform as well as the previous dynamic model in fitting known inhibitors of HIV-1 intergrase. To test the applicability of the dynamic pharmacophore method and the assumption that any reliable source of protein conformations is applicable, we have now developed a second dynamic pharmacophore model based on the two crystal structures also used for the development of the static models. Though the dynamic model based on the two crystal structures does not fit as many known inhibitors as the previous: dynamic model, it is a significant improvement over the static models. Even better performance is expected with the addition of new crystal structures as they become available. However, it is notable that using only two structures leads to great improvement in the models.