基于结构的虚拟筛选鉴定和鉴定 DC07090 作为新型有效的小分子抑制剂对人肠道病毒 71 3C 蛋白酶的抑制作用。
Identification and biochemical characterization of DC07090 as a novel potent small molecule inhibitor against human enterovirus 71 3C protease by structure-based virtual screening.
机构信息
Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Rd, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, 100 Haike Rd, Pudong, Shanghai 201210, China.
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, 38 Xueyuan Rd, Beijing 100191, China; University of Chinese Academy of Sciences, No.19A Yuquan Rd, Beijing 100049, China.
出版信息
Eur J Med Chem. 2016 Nov 29;124:981-991. doi: 10.1016/j.ejmech.2016.10.019. Epub 2016 Oct 11.
Hand, foot and mouth disease (HFMD) is a serious, highly contagious disease. HFMD caused by Enterovirus 71 (EV71), results in severe complications and even death. The pivotal role of EV71 3C in the viral life cycle makes it an attractive target for drug discovery and development to treat HFMD. In this study, we identified novel EV71 3C inhibitors by docking-based virtual screening. Totally 50 compounds were selected to test their inhibitory activity against EV71 3C. The best inhibitor DC07090 exhibited the inhibition potency with an IC value of 21.72 ± 0.95 μM without apparent toxicity (CC > 200 μM). To explore structure-activity relationship of DC07090, 15 new derivatives were designed, synthesized and evaluated in vitro enzyme assay accordingly. Interestingly, four compounds showed inhibitory activities against EV71 3C and only DC07090 inhibited EV71 replication with an EC value of 22.09 ± 1.07 μM. Enzyme inhibition kinetic experiments showed that the compound was a reversible and competitive inhibitor. The Ki value was determined to be 23.29 ± 12.08 μM. Further molecular docking, MD simulation and mutagenesis studies confirmed the binding mode of DC07090 and EV71 3C. Besides, DC07090 could also inhibit coxsackievirus A16 (CVA16) replication with an EC value of 27.76 ± 0.88 μM. Therefore, DC07090 represents a new non-peptidyl small molecule inhibitor for further development of antiviral therapy against EV71 or other picornaviruses.
手足口病（HFMD）是一种严重的、高度传染性疾病。由肠道病毒 71 型（EV71）引起的 HFMD 可导致严重并发症，甚至死亡。EV71 3C 在病毒生命周期中的关键作用使其成为药物发现和开发治疗 HFMD 的有吸引力的靶标。在这项研究中，我们通过基于对接的虚拟筛选鉴定了新型 EV71 3C 抑制剂。总共选择了 50 种化合物来测试它们对 EV71 3C 的抑制活性。最佳抑制剂 DC07090 表现出抑制效力，IC 值为 21.72 ± 0.95 μM，无明显毒性（CC > 200 μM）。为了探索 DC07090 的结构-活性关系，设计、合成了 15 种新的衍生物，并进行了相应的体外酶活性测定。有趣的是，四种化合物对 EV71 3C 具有抑制活性，只有 DC07090 能以 EC 值 22.09 ± 1.07 μM 抑制 EV71 复制。酶抑制动力学实验表明，该化合物是一种可逆和竞争性抑制剂。Ki 值为 23.29 ± 12.08 μM。进一步的分子对接、MD 模拟和突变研究证实了 DC07090 与 EV71 3C 的结合模式。此外，DC07090 还能以 EC 值 27.76 ± 0.88 μM 抑制柯萨奇病毒 A16（CVA16）的复制。因此，DC07090 代表了一种新的非肽小分子抑制剂，可进一步开发针对 EV71 或其他小核糖核酸病毒的抗病毒治疗方法。
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