Laboratory of Natural Products & Drug Discovery, Department of Basic Science, Universidad de La Frontera, Av. Francisco Salazar 01145, 4780000 Temuco, Chile.
Universidad de Concepción, Departamento de Microbiología, Laboratorio de Investigación en Agentes Antibacterianos (LIAA), Barrio Universitario S/N, 160-C 1807 Concepción, Chile.
Biomolecules. 2020 Jul 24;10(8):1101. doi: 10.3390/biom10081101.
species cause an opportunistic yeast infection called Candidiasis, which is responsible for more than 50,000 deaths every year around the world. Effective treatments against candidiasis caused by non-albicans species such as and are limited due to severe resistance to conventional antifungal drugs. Natural drimane sesquiterpenoids have shown promising antifungal properties against yeast and have emerged as valuable candidates for developing new candidiasis therapies. In this work, we isolated isodrimeninol () from barks of and used it as starting material for the hemi-synthesis of four sesquiterpenoids by oxidation with pyridinium chlorochromate (PCC). The structure of the products (, , and ) was elucidated by 1D and 2D NMR spectroscopy resulting in being a novel compound. Antifungal activity assays against and revealed that exhibited an increased activity (IC of 75 μg/mL) compared to (IC of 125 μg/mL) in all yeast strains. The antifungal activity of and was rationalized in terms of their capability to inhibit lanosterol 14-alpha demethylase using molecular docking, molecular dynamics simulations, and MM/GBSA binding free energy calculations. In silico analysis revealed that and bind to the outermost region of the catalytic site of 14-alpha demethylase and block the entrance of lanosterol () to the catalytic pocket. Binding free energy estimates suggested that forms a more stable complex with the enzyme than , in agreement with the experimental evidence. Based on this new approach it is possible to design new drimane-type sesquiterpenoids for the control of species as inhibitors of 14-alpha demethylase.
非白念珠菌属物种会引起一种称为念珠菌病的机会性酵母感染，每年在全球造成超过 5 万人死亡。由于对传统抗真菌药物的严重耐药性，针对 和 等非白念珠菌属物种引起的念珠菌病的有效治疗方法有限。天然的角鲨烯倍半萜类化合物对 酵母表现出有希望的抗真菌特性，并已成为开发新的念珠菌病治疗方法的有价值的候选药物。在这项工作中，我们从 的树皮中分离出异杜松烯醇（），并将其用作通过吡啶氯铬酸盐（PCC）氧化合成四个倍半萜烯的半合成起始原料。通过 1D 和 2D NMR 光谱阐明了产物（，，和）的结构，结果表明是一种新化合物。对 和 的抗真菌活性测定表明，与 （IC 为 125 μg/mL）相比，（IC 为 75 μg/mL）在所有酵母菌株中均表现出更高的活性。通过分子对接、分子动力学模拟和 MM/GBSA 结合自由能计算，根据它们抑制羊毛甾醇 14-α 脱甲基酶的能力，合理化了 和 的抗真菌活性。计算机分析表明，和与 14-α 脱甲基酶的催化部位的最外层结合，并阻止羊毛甾醇（）进入催化口袋。结合自由能估算表明，与酶形成更稳定的复合物，而不是 ，这与实验证据一致。基于这种新方法，可以设计新型角鲨烯型倍半萜类化合物作为 14-α 脱甲基酶抑制剂来控制 物种。
