{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T08:21:59Z","timestamp":1769588519411,"version":"3.49.0"},"reference-count":53,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2019,4,13]],"date-time":"2019-04-13T00:00:00Z","timestamp":1555113600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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\u2013Barr\u00e9 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 \u03bcM and 15.2 \u03bcM, respectively). Binding mode analysis, absolute binding free energy calculation, and structure\u2013activity 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.<\/jats:p>","DOI":"10.3390\/molecules24081465","type":"journal-article","created":{"date-parts":[[2019,4,15]],"date-time":"2019-04-15T11:15:58Z","timestamp":1555326958000},"page":"1465","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Discovery and Computational Analyses of Novel Small Molecule Zika Virus Inhibitors"],"prefix":"10.3390","volume":"24","author":[{"given":"Siyu","family":"Zhu","sequence":"first","affiliation":[{"name":"School of Life Sciences, Tsinghua University, Beijing 100084, China"},{"name":"Department of Medicine, Division of Infectious Diseases, School of Medicine, University of California San Diego, La Jolla, CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chaozai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, School of Medicine, University of California San Diego, La Jolla, CA 92037, USA"},{"name":"School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lina S.","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, School of Medicine, University of California San Diego, La Jolla, CA 92037, USA"},{"name":"College of Arts and Sciences, Cornell University, Ithaca, NY 14853, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xing-Quan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, School of Medicine, University of California San Diego, La Jolla, CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Life and Health Sciences, Chinese University of Hong Kong, Shenzhen 518172, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiong","family":"Fang","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Tsinghua University, Beijing 100084, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Nobel Institute of Biomedicine, Zhuhai 519000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meixian","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, School of Medicine, University of California San Diego, La Jolla, CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert T.","family":"Schooley","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, School of Medicine, University of California San Diego, La Jolla, CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziwei","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Tsinghua University, Beijing 100084, China"},{"name":"Department of Medicine, Division of Infectious Diseases, School of Medicine, University of California San Diego, La Jolla, CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"An","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, School of Medicine, University of California San Diego, La Jolla, CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/0035-9203(52)90042-4","article-title":"Zika virus. I. Isolations and serological specificity","volume":"46","author":"Dick","year":"1952","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1056\/NEJMra1602113","article-title":"Zika virus","volume":"374","author":"Petersen","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"55","DOI":"10.15585\/mmwr.mm6503e1","article-title":"Zika Virus Spreads to New Areas\u2014Region of the Americas, May 2015\u2013January 2016","volume":"65","author":"Hennessey","year":"2016","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"601","DOI":"10.2105\/AJPH.2016.303113","article-title":"The Epidemic of Zika Virus-Related Microcephaly in Brazil: Detection, Control, Etiology, and Future Scenarios","volume":"106","author":"Teixeira","year":"2016","journal-title":"Am. J. Public Health"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/S0140-6736(16)00006-4","article-title":"Zika virus in brazil and macular atrophy in a child with microcephaly","volume":"387","author":"Ventura","year":"2016","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1080\/01652176.2016.1188333","article-title":"Zika virus\u2014Emergence, evolution, pathology, diagnosis, and control: Current global scenario and future perspectives\u2014A comprehensive review","volume":"36","author":"Singh","year":"2016","journal-title":"Vet. Q."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4864","DOI":"10.1128\/JVI.00252-16","article-title":"Zika virus: New clinical syndromes and its emergence in the western hemisphere","volume":"90","author":"Lazear","year":"2016","journal-title":"J. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"20720","DOI":"10.2807\/1560-7917.ES2014.19.9.20720","article-title":"Zika virus infection complicated by guillain-barre syndrome--case report, french polynesia, december 2013","volume":"19","author":"Oehler","year":"2014","journal-title":"Euro Surveill."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1002\/uog.15831","article-title":"Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: Tip of the iceberg?","volume":"47","author":"Malinger","year":"2016","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s12978-017-0285-6","article-title":"Zika virus infection in pregnancy: A systematic review of disease course and complications","volume":"14","author":"Chibueze","year":"2017","journal-title":"Reprod. Health"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1038\/nsmb.3213","article-title":"Zika virus ns1 structure reveals diversity of electrostatic surfaces among flaviviruses","volume":"23","author":"Song","year":"2016","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1038\/nsmb.3268","article-title":"Extended surface for membrane association in zika virus ns1 structure","volume":"23","author":"Brown","year":"2016","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1126\/science.aag2419","article-title":"Crystal structure of zika virus ns2b-ns3 protease in complex with a boronate inhibitor","volume":"353","author":"Lei","year":"2016","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1126\/science.aai9309","article-title":"Crystal structure of unlinked ns2b-ns3 protease from zika virus","volume":"354","author":"Zhang","year":"2016","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"13410","DOI":"10.1038\/ncomms13410","article-title":"Structure of the NS2b-NS3 protease from zika virus after self-cleavage","volume":"7","author":"Phoo","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1038\/nsmb.3258","article-title":"Structure of the ns3 helicase from zika virus","volume":"23","author":"Jain","year":"2016","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3097","DOI":"10.1016\/j.celrep.2016.08.091","article-title":"Structures of ns5 methyltransferase from zika virus","volume":"16","author":"Coloma","year":"2016","journal-title":"Cell Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/j.bbrc.2016.11.098","article-title":"Structure of the ns5 methyltransferase from zika virus and implications in inhibitor design","volume":"492","author":"Zhang","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e02202-16","DOI":"10.1128\/JVI.02202-16","article-title":"Zika virus methyltransferase: Structure and functions for drug design perspectives","volume":"91","author":"Coutard","year":"2017","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"14762","DOI":"10.1038\/ncomms14762","article-title":"Structure and function of the zika virus full-length ns5 protein","volume":"8","author":"Zhao","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1038\/nrmicro1928","article-title":"Architects of assembly: Roles of flaviviridae non-structural proteins in virion morphogenesis","volume":"6","author":"Murray","year":"2008","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1016\/j.str.2017.06.006","article-title":"Structural dynamics of zika virus ns2b-ns3 protease binding to dipeptide inhibitors","volume":"25","author":"Li","year":"2017","journal-title":"Structure"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1146\/annurev.biochem.76.052305.115300","article-title":"Structure and mechanism of helicases and nucleic acid translocases","volume":"76","author":"Singleton","year":"2007","journal-title":"Annu. Rev. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1186\/s12985-017-0761-1","article-title":"Inhibitors compounds of the flavivirus replication process","volume":"14","author":"Garcia","year":"2017","journal-title":"Virol. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2694","DOI":"10.3762\/bjoc.12.267","article-title":"Computational methods in drug discovery","volume":"12","author":"Leelananda","year":"2016","journal-title":"Beilstein. J. Org. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.2174\/1568026611313100005","article-title":"Open source software and web services for designing therapeutic molecules","volume":"13","author":"Singla","year":"2013","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.cbi.2006.12.006","article-title":"Computer-aided drug discovery and development (caddd): In silico-chemico-biological approach","volume":"171","author":"Kapetanovic","year":"2008","journal-title":"Chem. Biol. Interact."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Huang, Z. (2007). Drug Discovery Research: New Frontiers in the Post-Genomic Era, Wiley-Interscience.","DOI":"10.1002\/9780470131862"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.antiviral.2013.09.013","article-title":"Ten years of dengue drug discovery: Progress and prospects","volume":"100","author":"Lim","year":"2013","journal-title":"Antivir. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/nrgastro.2016.60","article-title":"Direct-acting antiviral agents for hepatitis c: Structural and mechanistic insights","volume":"13","author":"Gotte","year":"2016","journal-title":"Nat. Rev Gastroenterol. Hepatol."},{"key":"ref_31","first-page":"10505","article-title":"Molecular mechanism of divalent-metal-induced activation of ns3 helicase and insights into zika virus inhibitor design","volume":"44","author":"Cao","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1007\/s13238-016-0293-2","article-title":"Structural basis of zika virus helicase in recognizing its substrates","volume":"7","author":"Tian","year":"2016","journal-title":"Protein Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1007\/s13238-016-0275-4","article-title":"The crystal structure of zika virus helicase: Basis for antiviral drug design","volume":"7","author":"Tian","year":"2016","journal-title":"Protein Cell"},{"key":"ref_34","first-page":"1101","article-title":"Molecular dynamics simulations of zika virus ns3 helicase: Insights into rna binding site activity","volume":"22","author":"Mottin","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nm.4184","article-title":"Identification of small-molecule inhibitors of zika virus infection and induced neural cell death via a drug repurposing screen","volume":"22","author":"Xu","year":"2016","journal-title":"Nat. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.chom.2016.07.004","article-title":"A screen of fda-approved drugs for inhibitors of zika virus infection","volume":"20","author":"Barrows","year":"2016","journal-title":"Cell Host Microbe"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.antiviral.2017.04.015","article-title":"Characterization of the zika virus two-component ns2b-ns3 protease and structure-assisted identification of allosteric small-molecule antagonists","volume":"143","author":"Shiryaev","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_38","first-page":"727","article-title":"Purification of zika virus rna-dependent rna polymerase and its use to identify small-molecule zika inhibitors","volume":"72","author":"Xu","year":"2017","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.antiviral.2016.12.016","article-title":"Identification of novel small molecule inhibitors against ns2b\/ns3 serine protease from zika virus","volume":"139","author":"Lee","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Brecher, M., Li, Z., Liu, B., Zhang, J., Koetzner, C.A., Alifarag, A., Jones, S.A., Lin, Q., Kramer, L.D., and Li, H. (2017). A conformational switch high-throughput screening assay and allosteric inhibition of the flavivirus ns2b-ns3 protease. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006411"},{"key":"ref_41","unstructured":"Li, K., Frankowski, K.J., Hanson, A.M., Ndjomou, J., Shanahan, M.A., Mukherjee, S., Kolli, R., Shadrick, W.R., Sweeney, N.L., and Belon, C.A. (2010). Hepatitis C Virus NS3 Helicase Inhibitor Discovery. Probe Reports from the NIH Molecular Libraries Program, Bethesda."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.1093\/jac\/dks147","article-title":"Ivermectin is a potent inhibitor of flavivirus replication specifically targeting ns3 helicase activity: New prospects for an old drug","volume":"67","author":"Mastrangelo","year":"2012","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1902","DOI":"10.1128\/AAC.02251-12","article-title":"Novel benzoxazole inhibitor of dengue virus replication that targets the ns3 helicase","volume":"57","author":"Byrd","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.jmgm.2016.08.011","article-title":"In-silico screening for anti-zika virus phytochemicals","volume":"69","author":"Byler","year":"2016","journal-title":"J. Mol. Graph. Model."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"104","DOI":"10.5808\/GI.2016.14.3.104","article-title":"Virtual screening for potential inhibitors of ns3 protein of zika virus","volume":"14","author":"Sahoo","year":"2016","journal-title":"Genomics Inform."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Ramharack, P., and Soliman, M.E.S. (2017). Zika virus ns5 protein potential inhibitors: An enhanced in silico approach in drug discovery. J. Biomol. Struct. Dyn., 1\u201316.","DOI":"10.1080\/07391102.2017.1313175"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"16212","DOI":"10.1021\/jacs.6b10399","article-title":"Structural insight into ns5 of zika virus leading to the discovery of mtase inhibitors","volume":"138","author":"Stephen","year":"2016","journal-title":"J. Am. Chem. Soc."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/s12943-015-0346-9","article-title":"Identification of trail-inducing compounds highlights small molecule onc201\/tic10 as a unique anti-cancer agent that activates the trail pathway","volume":"14","author":"Allen","year":"2015","journal-title":"Mol. Cancer"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/S0021-5198(19)31666-X","article-title":"Studies on the ultrastructural distribution of h 3 -dimetacrine in rat cerebral cortex","volume":"22","author":"Ishitani","year":"1972","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1124\/jpet.103.052829","article-title":"Arylacetamide kappa-opioid receptor agonists produce a tonic- and use-dependent block of tetrodotoxin-sensitive and -resistant sodium currents in colon sensory neurons","volume":"307","author":"Joshi","year":"2003","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_51","first-page":"187","article-title":"Antiphosphodiesterase activity of papaveroline\/sulfonic acid. In vitro spectrophotometric determination","volume":"33","author":"Castellani","year":"1978","journal-title":"Farmacol. Prat."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1007\/s10822-011-9533-y","article-title":"Surflex-dock: Docking benchmarks and real-world application","volume":"26","author":"Spitzer","year":"2012","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"349","DOI":"10.3201\/eid1802.111224","article-title":"Zika virus infection, cambodia, 2010","volume":"18","author":"Heang","year":"2012","journal-title":"Emerg. Infect. Dis."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/8\/1465\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:45:13Z","timestamp":1760186713000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/8\/1465"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,13]]},"references-count":53,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2019,4]]}},"alternative-id":["molecules24081465"],"URL":"https:\/\/doi.org\/10.3390\/molecules24081465","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,13]]}}}