標題: Zika Virus NS3 Protease Pharmacophore Anchor Model and Drug Discovery
作者: Pathak, Nikhil
Kuo, Yi-Ping
Chang, Teng-Yuan
Huang, Chin-Ting
Hung, Hui-Chen
Hsu, John Tsu-An
Yu, Guann-Yi
Yang, Jinn-Moon
生物科技學系
生物資訊及系統生物研究所
Department of Biological Science and Technology
Institude of Bioinformatics and Systems Biology
公開日期: 2-Jun-2020
摘要: Zika virus (ZIKV) of the flaviviridae family, is the cause of emerging infections characterized by fever, Guillain-Barre syndrome (GBS) in adults and microcephaly in newborns. There exists an urgent unmet clinical need for anti-ZIKV drugs for the treatment of infected individuals. In the current work, we aimed at the promising virus drug target, ZIKV NS3 protease and constructed a Pharmacophore Anchor (PA) model for the active site. The PA model reveals a total of 12 anchors (E, H, V) mapped across the active site subpockets. We further identified five of these anchors to be critical core anchors (CEH1, CH3, CH7, CV1, CV3) conserved across flaviviral proteases. The ZIKV protease PA model was then applied in anchor-enhanced virtual screening yielding 14 potential antiviral candidates, which were tested by in vitro assays. We discovered FDA drugs Asunaprevir and Simeprevir to have potent anti-ZIKV activities with EC50 values 4.7 mu M and 0.4 mu M, inhibiting the viral protease with IC50 values 6.0 mu M and 2.6 mu M respectively. Additionally, the PA model anchors aided in the exploration of inhibitor binding mechanisms. In conclusion, our PA model serves as a promising guide map for ZIKV protease targeted drug discovery and the identified 'previr' FDA drugs are promising for anti-ZIKV treatments.
URI: http://dx.doi.org/10.1038/s41598-020-65489-w
http://hdl.handle.net/11536/155401
ISSN: 2045-2322
DOI: 10.1038/s41598-020-65489-w
期刊: SCIENTIFIC REPORTS
Volume: 10
Issue: 1
起始頁: 0
結束頁: 0
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