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目的：研究氮唑类抗真菌药物与其受体蛋白活性位点相互作用机理。方法：用随机构象搜寻和分子动力学模拟退火法确定１５个４种不同类型的氮唑类抗真菌药物最低能量构象；用活性类似物法限定药物分子药效基团之间的距离，搜寻到各化合物药效构象；将各化合物药效构象对接到白色念珠菌羊毛甾醇１４α去甲基化酶活性位点中。结果：４种结构类型的氮唑类药物在酶活性位点中有相似的对接位置；真菌和哺乳动物的活性位点结构特异性的残基分布在Ｆ螺旋Ｃ端、β６１和β６２区中；氮唑类抗真菌药物共同的卤代芳环结构落入相同的疏水空穴中，其中Ｙ１３２的侧链羟苯基结构可与抑制剂卤代芳环形成电子迁移复合物。结论：对接结果与已知ＳＡＲ分析结论相符，阐明了氮唑类药物与活性位点的氨基酸残基作用方式，探讨结构选择性药物的结构需求。
OBJECTIVE: To study the mechanism of the interaction between the azole antifungal drug and its receptor protein active site. METHODS: The lowest energy conformations of 15 different azole antifungal agents in 15 different types were determined by random conformation search and molecular dynamics simulated annealing. The active analogs were used to limit the distance between the pharmacophore groups. To the pharmacodynamic conformation of each compound; docking the pharmacodynamic conformation of each compound to the C. albicans lanosterol 14 alpha demethylase activity site. Results: The four structural types of azole drugs have similar docking positions in the enzyme active sites. The structurally specific residues of the active sites in fungi and mammals are distributed in the C-terminal of F-helix, β6-1 and β6-β 2 region. The common halogenated aromatic ring structures of azole antifungal agents fell into the same hydrophobic cavities, and the side chain hydroxyphenyl structures of Y132 could form electron transfer complexes with halogenated aromatic rings of inhibitors. CONCLUSION: The docking results are consistent with the known SAR analysis results. The mode of action of the azole drugs and active site amino acid residues is clarified, and the structural requirements of the structure-selective drugs are discussed.