Ferdosiyan Marziyeh, Sardari Soroush
Department of Biochemistry, Science and Research Branch, Islamic Azad University, Tehran, Iran.
Avicenna J Med Biotechnol. 2010 Jul;2(3):137-43.
A major group of drugs that have been approved for the therapy of systemic fungal infections are polyene antibiotics. Amphotericin B (AmB), one of the polyene antibiotics, has been used to treat serious systemic fungal infections by binding to sterols such as ergosterol in fungal cells membrane, and is believed to form pores in the membrane and create a transmembrane ion-channel. Since all eukaryotic cells contain sterols, using AmB can cause toxicity in mammalian cells; this is the most serious unwanted side effect. Therefore, there is still a need to develop suitable antifungal compounds to be entered in the drug development pipeline. In this study, we report the screening of various compounds from the Enhanced NCI database against ergosterol and cholesterol as receptors. The strategy employed is divided into two categories, screening and docking, respectively. Screening was performed using structure search based on AmB and molecular constraints to filter compounds with physico-chemical properties similar to the polyene macrolid antibiotics. The selected compounds were docked and scored to identify structurally novel ligands that make similar interactions to AmB. Our screening approach identified several molecules with high ranking criteria mentioned above. Among these compounds, two molecules, NSC 89270 and NSC 62792 were tested for their bioactivity against three fungal strains using broth microdilution assay that presented to have moderate antifungal activity against tested fungi. Thus, they could be possible lead compounds that grant further research on them to improve their potency and compare their mechanism of action in comparison to AmB.
已被批准用于治疗全身性真菌感染的一大类药物是多烯抗生素。两性霉素B（AmB）是多烯抗生素之一，它通过与真菌细胞膜中的麦角固醇等固醇结合来治疗严重的全身性真菌感染，并且被认为会在膜中形成孔并产生跨膜离子通道。由于所有真核细胞都含有固醇，使用AmB会对哺乳动物细胞产生毒性；这是最严重的不良副作用。因此，仍然需要开发适合进入药物研发流程的抗真菌化合物。在本研究中，我们报告了从增强型美国国立癌症研究所（NCI）数据库中筛选各种化合物，以麦角固醇和胆固醇作为受体。所采用的策略分为两类，分别是筛选和对接。筛选是基于AmB和分子限制条件进行结构搜索，以过滤出具有与多烯大环内酯抗生素相似物理化学性质的化合物。对所选化合物进行对接和评分，以鉴定与AmB具有相似相互作用的结构新颖的配体。我们的筛选方法识别出了几个符合上述高排名标准的分子。在这些化合物中，使用肉汤微量稀释法对两个分子NSC 89270和NSC 62792针对三种真菌菌株的生物活性进行了测试，结果显示它们对测试真菌具有中等抗真菌活性。因此，它们可能是有潜力的先导化合物，值得对其进行进一步研究以提高其效力，并与AmB比较其作用机制。
