CYP51靶酶氨基酸残基Y118、S378与新型唑类药物作用机制研究  

The research on the key amino acids Y118,S378 responsible for candida albicans sterol 14α-demethylase selective interaction with new azoles analogous

作　　者：陈双红[1,2] 盛春泉[2] 徐晓辉[2] 姜远英[2] 张万年[2] 何成[2] 

机构地区：[1]海军医学研究所,上海200433 [2]第二军医大学药学院,上海200433

出　　处：《中国药理学通报》2009年第9期1188-1192,共5页Chinese Pharmacological Bulletin

基　　金：国家自然基金重点资助项目(No30430750)

摘　　要：目的研究新筛选合成的唑类化合物A1、A3、E2、E8与功能氨基酸残基Y118、S378的相互作用,阐明靶酶与新型药物的作用机制,为特异性唑类抗真菌药物的合成和筛选提供理论依据。方法用微量液基稀释法和GC-MS法分别在细胞水平和离体酶水平研究5个化合物(氟康唑、艾迪康唑、A1、A3、E2、E8)对靶酶不同突变衍生体蛋白的MIC80值和相对抑酶活性,用Roman光谱法研究化合物与酶的结合能力。结果不同化合物对突变体酶的抑制效应有差异,与氟康唑相比艾迪康唑、A系和E系化合物的体外抗菌效果强,Y118突变体对受试药物艾迪康唑、A3、E8的敏感性较对氟康唑的作用效应明显下降;S378残基对A3、E8化合物选择性强于氟康唑和艾迪康唑。结论结果支持同源模建的研究结论,Y118、S378残基与化合物特定侧链的化学集团形成配位结合或其它的相互作用,增强酶与化合物的结合能力,提高了化合物的抗真菌活性。Aim To investigate the interaction of the amino acids YIlS, S378 of CYPS1 and the new azolcs analogous A1, A3, E2 and ES. And to elucidate the mechanism of the new compounds interaction with the target enzyme for advancing antifungal designing and screening. Methods The broth dilution antifungal susceptibility testing methods were used to test the MIC80,GC-MS was used to test the inhibition activity of new azoles to the wild type and mutants of CYP51, and the Roman-spectra was used to test the binding of the enzyme and the compounds. Results The inhibition activity of antifungal compounds to different mutant enzymes changed. Compared to fluconazole, the idioconazole, A and E series compounds had more potent antifungal activities to the wild type enzyme, but less to the mutants. The susceptibility of Y118 mutant markedly decreased to iodiconazole, A3, E8, while as the susceptibility of S378 mutant decreased more to A3, E8 compounds. Conclusion These findings supported the previous 3D-model conclusions, that the residues Yl18 ,S378 can target binding to the special structure of the synthesized compounds, which further increases the antifungal activity of those compounds.

关 键 词：白念珠菌 14 α-去甲基化酶 活性 唑类 抗真菌药 化合物 

分 类 号：R394.2[医药卫生—医学遗传学] R379.4[医药卫生—基础医学]