抗真菌药物的创新设计研究

Innovative design of novel antifungal agents

运用计算机辅助药物设计技术和分子生物学技术,建立了一套集分子设计、化学合成和分子筛选三大系统为一体的抗真菌药创新设计体系。其工作原理是:通过药效构象搜寻、3D-QSAR研究,建立了抗真菌药物与受体作用模型,预测设计高活性化合物;另一方面,根据抗真菌药靶酶——羊毛甾醇14α-去甲基化酶的已知序列,采用同源蛋白模建技术构建其三维结构,再通过药物-靶酶对接研究,确定活性位点,设计与活性位点最佳匹配的活性化合物;然后针对设计的化合物类型,研究建立一套科学的合成方法,完成化合物的合成;最后以靶酶为模型,建立一套快速准确的分子筛选方法,用筛选结果指导进一步的设计与合成,直至得到最佳的新化学单体(NCE)。将该体系用于抗真菌药物设计,获得了一个广谱、高效、低毒的抗真菌新药——艾迪康唑。

On the basis of the technology of computer aided drug design and molecular biology we have established a platform for novel antifungal drug design, in which molecular design system, chemical synthesis system and drug screening system were integrated. The basic principle of the platform are described as follows: Firstly, building the antif ungal drug-receptor interaction model based on the active conformation search and 3D-QSAR study,then predicting and designing more active compounds. On the other hand, constructing the 3D model of lanosterol 14α-demethylase by homology modeling and designing small molecule specific to the drug target by confirming the drug - binding site, studying the interaction mode of drug and target. Secondly, finding a feasible synthetic route for the designed compounds and synthesizing them. Lastly, building a fast and reliable drug screening system and testing the antif ungal activity of the synthesized compounds until finding the NCE. We have applied the platform to antifungal drug design and got a novel antifungal compound named 'andiconazole', with broader antifungal spectrum, better efficiency and lower toxicity.