Zika Virus NS3 Protease Pharmacophore Anchor Model and Drug Discovery

Nikhil Pathak, Yi Ping Kuo, Teng Yuan Chang, Chin Ting Huang, Hui Chen Hung, John Tsu An Hsu, Guann Yi Yu, Jinn-Moon Yang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


Zika virus (ZIKV) of the flaviviridae family, is the cause of emerging infections characterized by fever, Guillain-Barré 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 µM and 0.4 µM, inhibiting the viral protease with IC50 values 6.0 µM and 2.6 µM 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.

Original languageEnglish
Article number8929
Pages (from-to)1-17
Number of pages17
JournalScientific reports
Issue number1
StatePublished - 1 Dec 2020


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