Maccari Giorgio, Deodato Davide, Fiorucci Diego, Orofino Francesco, Truglio Giuseppina I, Pasero Carolina, Martini Riccardo, De Luca Filomena, Docquier Jean-Denis, Botta Maurizio
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100 Siena, Italy.
Department of Medical Biotechnology, University of Siena, I-53100 Siena, Italy.
Bioorg Med Chem Lett. 2017 Aug 1;27(15):3332-3336. doi: 10.1016/j.bmcl.2017.06.016. Epub 2017 Jun 10.
In the last ten years, we identified and developed a new therapeutic class of antifungal agents, the macrocyclic amidinoureas. These compounds are active against several Candida species, including clinical isolates resistant to currently available antifungal drugs. The mode of action of these molecules is still unknown. In this work, we developed an in-silico target fishing procedure to identify a possible target for this class of compounds based on shape similarity, inverse docking procedure and consensus score rank-by-rank. Chitinase enzyme emerged as possible target. To confirm this hypothesis a novel macrocyclic derivative has been produced, specifically designed to increase the inhibition of the chitinase. Biological evaluation highlights a stronger enzymatic inhibition for the new derivative, while its antifungal activity drops probably because of pharmacokinetic issues. Collectively, our data suggest that chitinase represent at least one of the main target of macrocyclic amidinoureas.
在过去十年中，我们鉴定并开发了一类新型抗真菌治疗药物——大环脒基脲。这些化合物对多种念珠菌具有活性，包括对现有抗真菌药物耐药的临床分离株。这些分子的作用模式仍然未知。在这项工作中，我们开发了一种计算机辅助的靶点搜寻程序，基于形状相似性、反向对接程序和逐级共识评分，来确定这类化合物的可能靶点。几丁质酶被认为是可能的靶点。为了证实这一假设，我们制备了一种新型大环衍生物，专门设计用于增强对几丁质酶的抑制作用。生物学评估表明，新衍生物对酶的抑制作用更强，但其抗真菌活性可能由于药代动力学问题而下降。总体而言，我们的数据表明几丁质酶至少是大环脒基脲的主要靶点之一。
