A multistep approach to structure-based drug design: studying ligand binding at the human neutrophil elastase.
A multistep approach to structure-based drug design: studying ligand binding at the human neutrophil elastase.
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DOI：
10.1021/jm0505720
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发表时间：
2006-02
影响因子：
7.3
通讯作者：
T. Steinbrecher;D. Case;A. Labahn
中科院分区：
文献类型：
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作者：
T. Steinbrecher;D. Case;A. Labahn
在这项研究中，我们表明，不同的理论方法的组合是一个可行的方法来计算新的配体的人中性粒细胞弹性蛋白酶的结合亲和力。这种蛋白酶降解弹性蛋白，并可能帮助中性粒细胞实现其免疫功能。异常高的人中性粒细胞弹性蛋白酶（HNE）水平涉及几种疾病;因此，HNE的抑制剂作为药物设计的靶点是令人感兴趣的。最近的一项研究表明，肉桂酸和肉桂基酯衍生物结合HNE，但从配体对接结果的DeltaG 0值显示出与从IC 50值计算的值没有相关性。为了准确计算结合亲和力，我们通过配体对接计算产生了可能的蛋白质配体复合物结构。对于每个配体，使用30个最可能的位置作为纳秒长度分子动力学模拟的起点。这些复杂的结构的结合自由能估计使用连续溶剂（MM-PBSA）的方法。这些结果，沿着从分子动力学运行的结构数据，允许识别一组类似的位置，作为天然蛋白质配体复合物结构的模型。该结构模型用于进行热力学积分（TI）计算，以获得类似配体与HNE的相对结合自由能。TI结果与测得的结合亲和力定量一致。因此，所提出的方法可以用于生成已知的HNE配体的可能的复杂结构，并使用这样的结构来计算小的配体修饰对配体结合的影响，可能导致具有改善的结合亲和力的新抑制剂。
In this study we show that a combination of different theoretical methods is a viable approach to calculate the binding affinities of new ligands for the human neutrophile elastase. This protease degrades elastin and likely aids neutrophils in fulfilling their immunological functions. Abnormally high human neutrophil elastase (HNE) levels are involved in several diseases; therefore, inhibitors of HNE are of interest as targets for drug design. A recent study has revealed that cinnamic acid and bornyl ester derivatives bind to HNE, but DeltaG0 values from ligand docking results exhibited no correlation with those calculated from the IC50 values. To accurately compute binding affinities, we generated possible protein ligand complex structures by ligand docking calculations. For each of the ligands, the 30 most likely placements were used as starting points of nanosecond length molecular dynamics simulations. The binding free energies for these complex structures were estimated using a continuum solvent (MM-PBSA) approach. These results, along with structural data from the molecular dynamics runs, allowed the identification of a group of similar placements that serve as a model for the natural protein ligand complex structure. This structural model was used to perform thermodynamic integration (TI) calculations to obtain the relative binding free energies of similar ligands to HNE. The TI results were in quantitative agreement with the measured binding affinities. Thus, the presented approach can be used to generate a probable complex structure for known ligands to HNE and to use such a structure to calculate the effects of small ligand modifications on ligand binding, possibly leading to new inhibitors with improved binding affinities.