通过整合计算和实验方法发现靶向恶性疟原虫DNA回旋酶B的强效抗疟疾药物
Discovery of Potent Antimalarial Agents Targeting Plasmodium falciparum DNA Gyrase B by Integrating Computational and Experimental Approaches.
摘要(中文译文)
耐药恶性疟原虫（Plasmodium falciparum）的全球传播，尤其是耐青蒿素虫株的出现，凸显了研发具有不同作用机制和更优治疗潜力的新型抗疟药物的迫切需求。本研究采用计算机模拟与体外实验相结合的综合策略，筛选对恶性疟原虫质体旋转酶B（PfGyrB）具有抑制活性的化合物。高通量虚拟筛选鉴定出与靶蛋白具有良好预测相互作用的命中化合物，随后通过生化ATP酶抑制实验和寄生虫生长抑制实验对其进行评估。UNC8153和盐酸非索非那定表现出时间依赖性抗疟原虫活性，在延长暴露条件下，96 h的IC值低于48 h。在第二个红细胞内周期中，UNC8153的抗疟原虫活性约为参考化合物新生霉素的25倍。形态学分析表明，在延长暴露条件下，第二个红细胞内周期中寄生虫发育受损。重要的是，UNC8153对耐青蒿素的C580Y虫株保留了抑制活性，且在所测试的实验条件下对HEK-293细胞表现出极低的细胞毒性。结构相似性分析表明，所鉴定的化合物在化学结构上不同于目前使用的抗疟药物，支持其结构新颖性。综上所述，这些发现将UNC8153确定为一个结构独特的新型抗疟原虫骨架，值得进一步开展机制学、药理学和体内评估。
Abstract
The global spread of drug-resistant Plasmodium falciparum, particularly artemisinin-resistant strains, underscores the urgent need for novel antimalarial agents with distinct mechanisms of action and improved therapeutic potential. In this study, we employed an integrated in silico and in vitro strategy to identify compounds with inhibitory activity against P. falciparum apicoplast Gyrase B (PfGyrB). High-throughput virtual screening identified hit compounds with favorable predicted interactions against the target protein, which were subsequently evaluated using biochemical ATPase inhibition and parasite growth inhibition assays. UNC8153 and Fexofenadine hydrochloride demonstrated time-dependent antiplasmodial activity, with lower IC values at 96 h than at 48 h under prolonged exposure conditions. UNC8153 exhibited greater antiplasmodial activity (~25-fold) than the reference compound novobiocin during the second intraerythrocytic cycle. Morphological analysis indicated impaired parasite development during the second intraerythrocytic cycle under prolonged exposure conditions. Importantly, UNC8153 retained inhibitory activity against the artemisinin-resistant C580Y strain and exhibited minimal cytotoxicity toward HEK-293 cells under the tested experimental conditions. Structural similarity analysis indicated that the identified compounds are chemically distinct from currently used antimalarial drugs, supporting their structural novelty. Collectively, these findings identify UNC8153 as a structurally distinct new antiplasmodial scaffold warranting further mechanistic, pharmacological, and in vivo evaluation.
如何引用
AMA
Biswajit Naik, Welka Sahu, Guneswar Sethi, Cherish Prashar, Gajendra Mohan Baldodiya, Jyoti Poswal, et al. Discovery of Potent Antimalarial Agents Targeting Plasmodium falciparum DNA Gyrase B by Integrating Computational and Experimental Approaches.. Chemical biology & drug design. 2026; doi:10.1111/cbdd.70364.
APA
Biswajit Naik, Welka Sahu, Guneswar Sethi, Cherish Prashar, Gajendra Mohan Baldodiya, Jyoti Poswal, et al (2026). Discovery of Potent Antimalarial Agents Targeting Plasmodium falciparum DNA Gyrase B by Integrating Computational and Experimental Approaches.. Chemical biology & drug design. https://doi.org/10.1111/cbdd.70364
GB/T 7714
Biswajit Naik, Welka Sahu, Guneswar Sethi, Cherish Prashar, Gajendra Mohan Baldodiya, Jyoti Poswal, et al. Discovery of Potent Antimalarial Agents Targeting Plasmodium falciparum DNA Gyrase B by Integrating Computational and Experimental Approaches.[J]. Chemical biology & drug design, 2026 doi:10.1111/cbdd.70364.
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