Differential inhibition of Candida albicans CYP51 with azole antifungal stereoisomers
Differential inhibition of Candida albicans CYP51 with azole antifungal stereoisomers
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DOI：
10.1111/j.1574-6968.1997.tb10303.x
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发表时间：
1997-04-01
影响因子：
2.1
通讯作者：
Kelly, SL
中科院分区：
文献类型：
--
作者：
Lamb, DC;Kelly, DE;Kelly, SL
唑类抗真菌化合物在农业和治疗真菌感染中是重要的，目标酶--甾醇14α-脱甲基酶(CyP51)是通过三氮唑N-4作为第六配体与N-1取代基以某种方式与脱辅基蛋白相互作用而被抑制的。在这里，我们使用酿酒酵母表达系统作为白色念珠菌的靶酶，研究了唑类抗真菌化合物SCH39304和四康唑对映体的结合情况。先前制作的一个分子模型为这些差异提供了定性解释。唑类抗真菌芳香族基团与Phe-233或-235的相互作用可能导致(R)-四康唑的活性较高，而SCH39304的(SS)-对映体的失活可能是由于亲水的磺酰基部分进入活性中心的疏水口袋时不相容造成的。
Azole antifungal compounds are important in agriculture and in the treatment of mycotic infection The target enzyme, sterol 14 alpha-demethylase (CYP51), is inhibited through binding of triazole N-4 to the haem of this P450, as a sixth ligand together with the N-1 substituent groups interacting in some way with the apoprotein. Here we use Saccharomyces cerevisiae expression systems for the target enzyme of Candida albicans to investigate binding of enantiomers of the azole antifungal compounds SCH39304 and tetraconazole. A molecular model produced previously provided qualitative explanations for these differences. Interaction of the azole antifungal aromatic group with Phe-233 or -235 may cause the higher activity for (R)-tetraconazole while inactivity of the (SS)-enantiomer of SCH39304 was predicted to result from incompatibility of the hydrophilic sulfonyl moiety when located into the hydrophobic pocket of the active site.