新型抗皮肤真菌病活性化合物的筛选与评价  

SCREENING AND EVALUATION OF NOVEL ACTIVE COMPOUNDS AGAINST DERMATOMYCOSIS

作　　者：王尚[1] 肖忠海[1] 彭辉[1] 牛超[1] 王静[1] 王涛[1] 李佩尧[1] 刘颖[1] 赵小玲[1] 汪海[1] 

机构地区：[1]军事医学科学院卫生学环境医学研究所,天津300050

出　　处：《解放军预防医学杂志》2015年第1期4-7,共4页Journal of Preventive Medicine of Chinese People's Liberation Army

基　　金：十二五重大专项(No.AWS11J003)

摘　　要：目的筛选抗皮肤真菌病活性化合物,并进行效果评价,为进一步研究新型抗真菌药物提供依据。方法基于计算机辅助设计-分子对接模型,通过Auto Dock软件模拟化合物与靶标的结合,确定待筛选化合物库;以氟康唑(FCZ)作为阳性对照,应用微量液基稀释法观察54个新型化合物库对8株标准菌株的抑制效果,通过酶标仪测定最低抑菌浓度(minimum inhibitory concentration,MIC)判断抑菌活性;并采用纸片扩散法评价活性化合物抑制白色念珠菌的体外量效关系。结果筛选出3个新型活性化合物(编号分别为b-ch3、p-8和p-10)对8株不同致病真菌均具有较好抑制作用,其中b-ch3对部分真菌菌株MIC均≤0.125μg/ml。纸片法评价结果显示,随着bch3浓度的升高,抑菌环直径在增加,具有较好的剂量依赖性。50 mg/L和100 mg/L b-ch3对白色念珠菌抑菌环直径明显大于相同剂量FCZ抑菌环直径(P<0.05)。b-ch3与β碳酸酐酶(β-CA)分子对接分析显示,两者间相互作用能为-16.60 k J/mol。结论成功筛选出有应用前景的新型抗皮肤真菌病新型化合物,为研发靶向β-CA的特异、安全、有效的皮肤真菌病防治药物打下基础。Objective To screen and evaluate new active compounds against dermatomycosis, so as to provide the basis for further studying new anti-dermatomycosis drug. Methods Based on molecular docking similuated method ,the screening compound library was selected . The inhibition of 54 novel compounds on pathogenic fungi was observed by the broth microdilution method, and flueonazole （FCZ）was used as positive control. To identify active compounds,the minimum inhibitory concentration （MIC） was measured by Enzyme Mark Instrument. Then the doseeffect of active compounds was preliminarily verified through the paper diffusion method. Results Three active compounds（ b-oh3 ,p-8 ,and p-10） were confirmed to inhibit 8 strains of pathogenic fungi effectively. The inhibition of b- ch3 （MIC ≤0. 125 μg/ml） on Candida albicans was significantly effective. Paper method showed that the diameter of inhibitory area increased with the concentration elevation. And the diameters of inhibitory areas of 50 mg/L,and 100 mg/L b-ch3 on Candida albicans were significantly bigger than those of FCZ with the same concentrations （P〈0. 05 ）. In addition, analysis of interaction showed that b-ch3 could bind to 13 carbonic anhydrase （13-CA） specifically（ interactive energy ： -16. 60 kJ/mol）. Conclusion The novel and promising compounds to inhibit pathogenic fungi were successfully obtained ;which paved the way for developing specific, safe, and effective anti-dermato-fungal drugs.

关 键 词：皮肤真菌病 真菌 β碳酸酐酶 最低抑菌浓度 

分 类 号：R756[医药卫生—皮肤病学与性病学]