Yang Yiqing, Tang Tongke, Li Xiaolu, Michel Thomas, Ling Liqin, Huang Zhenghui, Mulaka Maruthi, Wu Yue, Gao Hongying, Wang Liguo, Zhou Jing, Meunier Brigitte, Ke Hangjun, Jiang Lubin, Rao Yu
MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing 100084, China.
Unit of Human Parasite Molecular and Cell Biology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Acta Pharm Sin B. 2021 Sep;11(9):2900-2913. doi: 10.1016/j.apsb.2021.05.008. Epub 2021 May 20.
Malaria still threatens global health seriously today. While the current discoveries of antimalarials are almost totally focused on single mode-of-action inhibitors, multi-targeting inhibitors are highly desired to overcome the increasingly serious drug resistance. Here, we performed a structure-based drug design on mitochondrial respiratory chain of and identified an extremely potent molecule, RYL-581, which binds to multiple protein binding sites of simultaneously (allosteric site of type II NADH dehydrogenase, Q and Q sites of cytochrome ). Antimalarials with such multiple targeting mechanism of action have never been reported before. RYL-581 kills various drug-resistant strains and shows good solubility as well as activity. This structure-based strategy for designing RYL-581 from starting compound may be helpful for other medicinal chemistry projects in the future, especially for drug discovery on membrane-associated targets.
疟疾如今仍严重威胁着全球健康。虽然目前抗疟药物的发现几乎完全集中在单一作用模式抑制剂上，但为克服日益严重的耐药性，人们迫切需要多靶点抑制剂。在此，我们对[具体物种]的线粒体呼吸链进行了基于结构的药物设计，并鉴定出一种极具效力的分子RYL-581，它能同时结合[具体物种]的多个蛋白质结合位点（II型NADH脱氢酶的变构位点、细胞色素[具体名称]的Q和Q位点）。此前从未报道过具有这种多靶点作用机制的抗疟药物。RYL-581能杀死各种耐药菌株，且具有良好的溶解性和[具体活性]。从起始化合物设计RYL-581的这种基于结构的策略可能对未来其他药物化学项目有所帮助，尤其是针对与膜相关靶点的药物发现。
