化学
吲哚试验
神经氨酸酶
神经氨酸酶抑制剂
分子模型
芯(光纤)
立体化学
组合化学
生物化学
酶
2019年冠状病毒病(COVID-19)
复合材料
病理
医学
材料科学
传染病(医学专业)
疾病
作者
Andrey Tsedilin,Michaela Schmidtke,Natalia Monakhova,И. А. Ленева,Irina N. Falynskova,Maria G. Khrenova,Thomas R. Lane,Sean Ekins,Vadim Makarov
标识
DOI:10.1016/j.ejmech.2024.116768
摘要
Influenza viruses that cause seasonal and pandemic flu are a permanent health threat. The surface glycoprotein, neuraminidase, is crucial for the infectivity of the virus and therefore an attractive target for flu drug discovery campaigns. We have designed and synthesized more than 40 3-indolinone derivatives. We mainly investigated the role of substituents at the 2 position of the core as well as the introduction of substituents or a nitrogen atom in the fused phenyl ring of the core for inhibition of influenza virus neuraminidase activity and replication in vitro and in vivo. After evaluating the compounds for their ability to inhibit the viral neuraminidase, six potent inhibitors 3c, 3e, 7c, 12o, 12v, 18d were progressed to evaluate for cytotoxicity and inhibition of influenza virus A/PR/8/34 replication in in MDCK cells. Two hit compounds 3e and 12o were tested in an animal model of influenza virus infection. Molecular mechanism of the 3-indolinone derivatives interactions with the neuraminidase was revealed in molecular dynamic simulations. Proposed inhibitors bind to the 430-cavity that is different from the conventional binding site of commercial compounds. The most promising 3-indolinone inhibitors demonstrate stronger interactions with the neuraminidase in molecular models that supports proposed binding site.
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