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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 anti-dermatomycosis active compounds and evaluate their effects, providing the basis for further research on new antifungal drugs. Methods Based on the computer-aided design-molecular docking model, Auto Dock software was used to simulate the combination of compounds and targets to determine the compound libraries to be screened. Fluconazole (FCZ) was used as a positive control, and 54 new compound libraries The antibacterial activity against eight strains of standard strains was determined by measuring the minimum inhibitory concentration (MIC) with microplate reader. The in vitro dosimetric-activity relationship of the active compounds against Candida albicans was evaluated by disk diffusion method. Results Three new active compounds (numbered as b-ch3, p-8 and p-10, respectively) were screened against 8 different pathogenic fungi. Among them, the MIC of b-ch3 to some fungal strains was ≤0.125 μg / ml. The results of the paper method showed that with the increase of bch3 concentration, the diameter of the bacteriostatic ring increased with a good dose-dependent manner. The diameters of bacteriuria rings of Candida albicans at 50 mg / L and 100 mg / L b-ch3 were significantly larger than those at the same dose of FCZ (P <0.05). The docking analysis of b-ch3 and β-carbonic anhydrase (β-CA) showed that the interaction energy between them was -16.60 kJ / mol. Conclusion The novel compounds against dermatophytosis were successfully screened out for application in the prevention and treatment of dermatophytosis, which is a specific, safe and effective method for the treatment of β-CA.