Identification and biochemical characterization of DC07090 as a novel potent small molecule inhibitor against human enterovirus 71 3C protease by structure-based virtual screening,European Journal of Medicinal Chemistry

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Identification and biochemical characterization of DC07090 as a novel potent small molecule inhibitor against human enterovirus 71 3C protease by structure-based virtual screening
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2016-10-11 , DOI: 10.1016/j.ejmech.2016.10.019
Guang-Hui Ma ₁ , Yan Ye ₂ , Dan Zhang ₃ , Xin Xu ₄ , Pei Si ₅ , Jian-Long Peng ₆ , Yong-Long Xiao ₄ , Rui-Yuan Cao ₇ , Yu-Ling Yin ₄ , Jing Chen ₄ , Lin-Xiang Zhao ₈ , Yu Zhou ₄ , Wu Zhong ₇ , Hong Liu ₄ , Xiao-Min Luo ₉ , Li-Li Chen ₄ , Xu Shen ₄

Affiliation

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.
Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Culture Rd, Shenyang 110016, China.
Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; College of Life and Environmental Sciences, Shanghai Normal University, 100 Guilin Road, Shanghai 200234, 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.
Beijing Institute of Pharmacology and Toxicology, 27 Taiping Rd., Beijing 100850, China.
Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Culture Rd, Shenyang 110016, 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.

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^pro 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^pro inhibitors by docking-based virtual screening. Totally 50 compounds were selected to test their inhibitory activity against EV71 3C^pro. The best inhibitor DC07090 exhibited the inhibition potency with an IC₅₀ value of 21.72 ± 0.95 μM without apparent toxicity (CC₅₀ > 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^pro and only DC07090 inhibited EV71 replication with an EC₅₀ 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^pro. Besides, DC07090 could also inhibit coxsackievirus A16 (CVA16) replication with an EC₅₀ 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.

中文翻译：

通过基于结构的虚拟筛选对 DC07090 作为新型有效的人肠道病毒 71 3C 蛋白酶小分子抑制剂进行鉴定和生化表征

手足口病（HFMD）是一种严重的、高度传染性的疾病。由肠道病毒71型（EV71）引起的手足口病会导致严重的并发症，甚至死亡。 EV71 3C ^pro在病毒生命周期中的关键作用使其成为治疗手足口病药物发现和开发的有吸引力的靶标。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 ^pro抑制剂。共选取50个化合物测试其对EV71 3C ^pro的抑制活性。最好的抑制剂DC07090表现出抑制效力，IC ₅₀值为21.72 ± 0.95 μM，且无明显毒性（CC ₅₀ > 200 μM）。为了探索DC07090的构效关系，设计、合成了15种新的衍生物，并相应地进行了体外酶测定评估。有趣的是，四种化合物对 EV71 3C ^pro显示出抑制活性，只有 DC07090 抑制 EV71 复制，EC ₅₀值为 22.09 ± 1.07 μM。酶抑制动力学实验表明该化合物是一种可逆的竞争性抑制剂。 Ki 值测定为 23.29 ± 12.08 μM。进一步的分子对接、MD模拟和诱变研究证实了DC07090和EV71 3C ^pro的结合模式。此外，DC07090还可以抑制柯萨奇病毒A16（CVA16）复制，EC ₅₀值为27.76 ± 0.88 μM。因此，DC07090代表了一种新的非肽基小分子抑制剂，可用于进一步开发针对EV71或其他小核糖核酸病毒的抗病毒疗法。

更新日期：2016-10-11

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