Interactions of Ligands with Class-II HMG-CoA Reductase of Streptococcus Pneumoniae by Homology Modeling and Molecular Dynamic Simulations
Interactions of Ligands with Class-II HMG-CoA Reductase of Streptococcus Pneumoniae by Homology Modeling and Molecular Dynamic Simulations
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通过同源建模和分子动力学模拟研究配体与肺炎链球菌II类HMG-CoA还原酶的相互作用
DOI：
10.1166/jctn.2007.2423
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发表时间：
2007-11
期刊：
影响因子：
--
通讯作者：
万坚
中科院分区：
文献类型：
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作者：
万坚
来自细菌病原体的II类HMG-CoA还原酶（II类HMGR）的功能性甲羟戊酸途径对于这些病原体的存活是必不可少的。因此，II类HMGR已被确定为抗生素的最重要靶点之一，可用于治疗由这些病原体引起的感染。为了设计新型II类HMGR抑制剂，我们利用同源建模和分子动力学模拟程序建立了肺炎链球菌II类HMGR三维二聚体结构的理论模型。随后，我们通过将洛伐他汀和HMG对接到所提出的三维二聚体结构中来分析配体-受体相互作用。结果表明，洛伐他汀与HMG的结合模型与晶体结构上的结合模型相似。这些结果进一步证实了II类HMGR同源性模型的可靠性，也表明了对接过程中所选择的参数和方法是合理的。在没有晶体结构的情况下，我们的研究提供了对结构及其与底物和配体结合的早期洞察，从而为鉴定或合理设计更有效的抑制剂提供了新的起点。
The functional mevalonate pathway of the Class-II HMG-CoA reductase (Class-II HMGR) from bacterial pathogens is essential for the survival of these pathogens. So, Class-II HMGR has been identified as one of the most important targets of antibiotics, which could be used to treat infections caused by these pathogens. With the aim of designing novel inhibitors of Class-II HMGR, we created a theoretical model of the three-dimensional dimmer structure of Class-II HMGR from Streptococcus pneumoniae by using homology modeling and molecular dynamic simulation procedures. Subsequently, we analyzed ligand–receptor interactions by docking lovastatin and HMG into the proposed three-dimensional dimmer structure. Results revealed that the binding model of lovastatin and HMG were similar to the binding model in their crystal structure. These results further confirmed the reliability of the homology model of Class-II HMGR, and also showed that the selected parameter and method for the docking process were reasonable. In the absence of a crystal structure, our study provides an early insight into the structure and its binding to the substrate and ligand, thus providing a new starting point for the identification or rational design of more potent inhibitors.