烟曲霉羊毛甾醇14α-去甲基化酶的三维同源结构建模及其分子对接研究

Homology Modeling of Aspergillus Fumigatus CYP51 and Its Molecular Docking Study with Voriconazole

探究烟曲霉羊毛甾醇14α-去甲基化酶活性位点的结构特征.首次采用同源建模的方法构建了烟曲霉羊毛甾醇14α-去甲基化酶的三维结构,并通过Ramachandran和Profile-3D图验证了模型的可靠性.然后,利用已知的共结晶配体结构,准确定位了14α-去甲基化酶的活性位点,让伏立康唑与靶点进行对接.通过柔性分子对接方法首次阐明了14α-去甲基化酶抑制剂与靶酶活性位点的相互作用模式,明确了14α-去甲基化酶与该类抑制剂结合时起重要作用的氨基酸残基.本研究为基于烟曲霉14α-去甲基化酶三维结构的药物靶点设计提供重要的参考信息,同时也为抗真菌药的发展奠定坚实的理论基础.

In order to further explore the structural features of the active site of 14α-demethylase(CYP51)of Aspergillus fumigatus.Homologous 3D model of Aspergillus fumigatus CYP51 was constructed by the protein crystal structure of Homo sapiensandTrypanosoma cruzi,and the reliability of the model was assessed by Ramachandran plot and Profile-3D analysis.The active site of Aspergillus fumigatus CYP51 was defined by the co-crystallized ligand of fluconazole.Finally,the voriconazole was docked to the homology model CYP51.The binding pattern was predicted by the affinity module revealed that important residues interacted with the voriconazole.The study further provided the refinement of CYP51 inhibitor binding interaction that may be used as a basis for new structure-based design efforts and discovery of antifungal agents.