Discovery and Computational Analyses of Novel Small Molecule Zika Virus Inhibitors

Molecules

LinaS. Huang¹  Jing An¹  RobertT. Schooley¹  Chaozai Zhang¹  Meixian Wu¹  Xing-Quan Zhang¹  Jiao Zhou²  Siyu Zhu³  Xiong Fang³  Ziwei Huang³  Yan Xu⁴ 

[1] Department of Medicine, Division of Infectious Diseases, School of Medicine, University of California San Diego, La Jolla, CA 92037, USA;Nobel Institute of Biomedicine, Zhuhai 519000, China;School of Life Sciences, Tsinghua University, Beijing 100084, China;School of Life and Health Sciences, Chinese University of Hong Kong, Shenzhen 518172, China;

关键词: Zika virus;    flaviviruses;    structure-based virtual screening;    non-structural protein 3;    benzenediol;    tetrahydroxy pentanoate;   

DOI  :  10.3390/molecules24081465

来源: DOAJ

【 摘 要 】

Zika virus (ZIKV), one of the flaviviruses, has attracted worldwide attention since its large epidemics around Brazil. Association of ZIKV infection with microcephaly and neurological problems such as Guillain–Barré syndrome has prompted intensive pathological investigations. However, there is still a long way to go on the discovery of effective anti-ZIKV therapeutics. In this study, an in silico screening of the National Cancer Institute (NCI) diversity set based on ZIKV NS3 helicase was performed using a molecular docking approach. Selected compounds with drug-like properties were subjected to cell-based antiviral assays resulting in the identification of two novel lead compounds (named Compounds 1 and 2). They inhibited ZIKV infection with IC₅₀ values at the micro-molar level (8.5 μM and 15.2 μM, respectively). Binding mode analysis, absolute binding free energy calculation, and structure–activity relationship studies of these two compounds revealed their possible interactions with ZIKV NS3 helicase, suggesting a mechanistic basis for further optimization. These two novel small molecules may represent new leads for the development of inhibitory drugs against ZIKV.

【 授权许可】

Unknown