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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\u00a0anchors 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 <jats:italic>in vitro<\/jats:italic> assays. We discovered FDA drugs Asunaprevir and Simeprevir to have potent anti-ZIKV activities with EC<jats:sub>50<\/jats:sub> values 4.7\u2009\u00b5M and 0.4\u2009\u00b5M, inhibiting the viral protease with IC<jats:sub>50<\/jats:sub> values 6.0\u2009\u00b5M and 2.6\u2009\u00b5M 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 \u2018previr\u2019 FDA drugs are promising for anti-ZIKV treatments.<\/jats:p>","DOI":"10.1038\/s41598-020-65489-w","type":"journal-article","created":{"date-parts":[[2020,6,2]],"date-time":"2020-06-02T10:06:02Z","timestamp":1591092362000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Zika Virus NS3 Protease Pharmacophore Anchor Model and Drug Discovery"],"prefix":"10.1038","volume":"10","author":[{"given":"Nikhil","family":"Pathak","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ping","family":"Kuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teng-Yuan","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin-Ting","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Chen","family":"Hung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Tsu-An","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guann-Yi","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinn-Moon","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,6,2]]},"reference":[{"key":"65489_CR1","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1111\/imj.13059","volume":"46","author":"CW Ong","year":"2016","unstructured":"Ong, C. 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