Drug repositioning is the process of discovery, validation and marketing of previously approved drugs for new indications. Our aim was drug repositioning, using ligand-based and structure-based computational methods, of compounds that are similar to two hit compounds previously selected by our group that show promising antifungal activity. Through the ligand-based method, 100 compounds from each of three databases (MDDR, DrugBank and TargetMol) were selected by the Tanimoto coefficient, as similar to LMM5 or LMM11. These compounds were analyzed by the scaffold trees, and up to 10 compounds from each database were selected. The structure-based method (molecular docking) using thioredoxin reductase as the target drug was performed as a complementary approach, resulting in six compounds that were tested in an in vitro assay. All compounds, particularly raltegravir, showed antifungal activity against the genus Paracoccidioides. Raltegravir, an antiviral drug, showed promising antifungal activity against the experimental murine paracoccidioidomycosis, with significant reduction of the fungal burden and decreased alterations in the lung structure of mice treated with 1 mg/kg of raltegravir. In conclusion, the combination of two in silico methods for drug repositioning was able to select an antiviral drug with promising antifungal activity for treatment of paracoccidioidomycosis.

中文翻译：

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重用方法确定了侵袭性真菌病的新治疗选择。

药物重新定位是发现，验证和销售先前批准的用于新适应症的药物的过程。我们的目标是使用基于配体和基于结构的计算方法对与我们小组先前选择的两种显示出有希望的抗真菌活性的命中化合物相似的化合物进行药物重新定位。通过基于配体的方法，通过Tanimoto系数从三个数据库（MDDR，DrugBank和TargetMol）的每一个中选择了100种化合物，类似于LMM5或LMM11。这些化合物通过支架树进行了分析，并且从每个数据库中最多选择了10种化合物。使用硫氧还蛋白还原酶作为靶标药物的基于结构的方法（分子对接）作为补充方法进行，得到了六种化合物，并在体外测定中进行了测试。所有化合物 特别是raltegravir，对Paracoccidioides属具有抗真菌活性。Raltegravir是一种抗病毒药，对实验性鼠副球孢子菌病具有良好的抗真菌活性，可显着降低真菌负荷，并减少用1 mg / kg raltegravir治疗的小鼠的肺部结构变化。总之，两种计算机模拟药物重定位方法的结合能够选择具有希望的抗真菌活性的抗病毒药物来治疗副球孢子菌病。可以显着降低真菌负荷，并减少用1 mg / kg raltegravir治疗的小鼠的肺部结构变化。总之，两种计算机模拟药物重定位方法的结合能够选择一种具有抗真菌活性的抗病毒药物，用于治疗副球孢子菌病。可以显着降低真菌负荷，并减少用1 mg / kg raltegravir治疗的小鼠的肺部结构变化。总之，两种计算机模拟药物重定位方法的结合能够选择具有希望的抗真菌活性的抗病毒药物来治疗副球孢子菌病。