2. Academic Validation
  3. Identification and biochemical characterization of DC07090 as a novel potent small molecule inhibitor against human enterovirus 71 3C protease by structure-based virtual screening

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

  • Eur J Med Chem. 2016 Nov 29;124:981-991. 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 9,  Wu Zhong 7,  Hong Liu 4,  Xiao-Min Luo 10,  Li-Li Chen 11,  Xu Shen 4
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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.
  • 4 Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 5 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.
  • 6 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.
  • 7 Beijing Institute of Pharmacology and Toxicology, 27 Taiping Rd., Beijing 100850, China.
  • 8 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Culture Rd, Shenyang 110016, China.
  • 9 Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: [email protected].
  • 10 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. Electronic address: [email protected].
  • 11 Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: [email protected].
PMID: 27776325 DOI: 10.1016/j.ejmech.2016.10.019
Abstract

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 3Cpro 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 3Cpro inhibitors by docking-based virtual screening. Totally 50 compounds were selected to test their inhibitory activity against EV71 3Cpro. 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 3Cpro 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 3Cpro. 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.

Keywords

EV71 3C(pro); HFMD; Non-peptidyl inhibitor; Virtual screening.

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