{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T03:49:59Z","timestamp":1791344999534,"version":"4.3.1"},"reference-count":64,"publisher":"Elsevier BV","issue":"10","license":[{"start":{"date-parts":[[2018,10,1]],"date-time":"2018-10-01T00:00:00Z","timestamp":1538352000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2018,10,1]],"date-time":"2018-10-01T00:00:00Z","timestamp":1538352000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2019,10,2]],"date-time":"2019-10-02T00:00:00Z","timestamp":1569974400000},"content-version":"vor","delay-in-days":366,"URL":"http:\/\/www.elsevier.com\/open-access\/userlicense\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01 AI085051"],"award-info":[{"award-number":["R01 AI085051"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["F31 GM119345"],"award-info":[{"award-number":["F31 GM119345"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["cell.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Structure"],"published-print":{"date-parts":[[2018,10]]},"DOI":"10.1016\/j.str.2018.07.004","type":"journal-article","created":{"date-parts":[[2018,8,23]],"date-time":"2018-08-23T10:49:04Z","timestamp":1535021344000},"page":"1360-1372.e5","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":23,"title":["Molecular Mechanism of Resistance in a Clinically Significant Double-Mutant Variant of HCV NS3\/4A Protease"],"prefix":"10.1016","volume":"26","author":[{"given":"Ashley N.","family":"Matthew","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Leidner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Newton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christos J.","family":"Petropoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akbar","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nese","family":"KurtYilmaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia A.","family":"Schiffer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.str.2018.07.004_bib1","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1107\/S0907444909052925","article-title":"PHENIX: a comprehensive Python-based system for macromolecular structure solution","volume":"66","author":"Adams","year":"2010","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"10.1016\/j.str.2018.07.004_bib2","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1021\/cb400100g","article-title":"Evaluating the role of macrocycles in the susceptibility of hepatitis C virus NS3\/4A protease inhibitors to drug resistance","volume":"8","author":"Ali","year":"2013","journal-title":"ACS Chem. Biol."},{"key":"10.1016\/j.str.2018.07.004_bib3","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1111\/liv.13027","article-title":"Direct-acting antivirals for the treatment of hepatitis C virus infection: optimizing current IFN-free treatment and future perspectives","volume":"36","author":"Asselah","year":"2016","journal-title":"Liver Int."},{"key":"10.1016\/j.str.2018.07.004_bib4","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1002\/jcc.20292","article-title":"Integrated modeling program, applied chemical theory (IMPACT)","volume":"26","author":"Banks","year":"2005","journal-title":"J.\u00a0Comput. Chem."},{"key":"10.1016\/j.str.2018.07.004_bib5","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/S2468-1253(16)30181-9","article-title":"Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study","volume":"2","author":"Blach","year":"2017","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"10.1016\/j.str.2018.07.004_bib6","doi-asserted-by":"crossref","first-page":"2134","DOI":"10.1056\/NEJMoa1613512","article-title":"Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection","volume":"376","author":"Bourliere","year":"2017","journal-title":"N.\u00a0Engl. J. Med."},{"key":"10.1016\/j.str.2018.07.004_bib7","doi-asserted-by":"crossref","unstructured":"Bowers, K.J., Chow, E., Xu, H., Dror, R.O., Eastwood, M.P., Gregerson, B.A., Klepeis, J.L., Kolossvary, I., Moraes, M.A., Sacerdoti, F.D., et\u00a0al. (2006). Scalable algorithms for molecular dynamics simulations on commodity clusters. Paper presented at: Proceedings of the ACM\/IEEE Conference on Supercomputing (SC06) (Tampa, Florida, United States).","DOI":"10.1145\/1188455.1188544"},{"key":"10.1016\/j.str.2018.07.004_bib8","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1038\/355472a0","article-title":"Free R value: a novel statistical quantity for assessing the accuracy of crystal structures","volume":"355","author":"Brunger","year":"1992","journal-title":"Nature"},{"key":"10.1016\/j.str.2018.07.004_bib9","doi-asserted-by":"crossref","first-page":"W375","DOI":"10.1093\/nar\/gkm216","article-title":"MolProbity: all-atom contacts and structure validation for proteins and nucleic acids","volume":"35","author":"Davis","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.str.2018.07.004_bib10","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1107\/S0907444904019158","article-title":"Coot: model-building tools for molecular graphics","volume":"60","author":"Emsley","year":"2004","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"10.1016\/j.str.2018.07.004_bib11","doi-asserted-by":"crossref","first-page":"8577","DOI":"10.1063\/1.470117","article-title":"A smooth particle mesh Ewald method","volume":"103","author":"Essmann","year":"1995","journal-title":"J.\u00a0Chem. Phys."},{"key":"10.1016\/j.str.2018.07.004_bib12","doi-asserted-by":"crossref","first-page":"637","DOI":"10.7326\/M16-2575","article-title":"Oral direct-acting agent therapy for hepatitis c\u00a0virus infection: a systematic review","volume":"166","author":"Falade-Nwulia","year":"2017","journal-title":"Ann. Intern. Med."},{"key":"10.1016\/j.str.2018.07.004_bib13","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1056\/NEJMoa020047","article-title":"Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection","volume":"347","author":"Fried","year":"2002","journal-title":"N.\u00a0Engl. J. Med."},{"key":"10.1016\/j.str.2018.07.004_bib14","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1111\/jvh.12552","article-title":"Efficacy and safety of grazoprevir\u00a0+ ribavirin for 12 or 24\u00a0weeks in treatment-naive patients with hepatitis C virus genotype 1 infection","volume":"23","author":"Gane","year":"2016","journal-title":"J.\u00a0Viral Hepat."},{"key":"10.1016\/j.str.2018.07.004_bib15","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1002\/hep.24641","article-title":"An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases","volume":"54","author":"Ghany","year":"2011","journal-title":"Hepatology"},{"key":"10.1016\/j.str.2018.07.004_bib16","doi-asserted-by":"crossref","first-page":"S45","DOI":"10.1016\/j.jhep.2014.07.027","article-title":"Global epidemiology and genotype distribution of the hepatitis C virus infection","volume":"61","author":"Gower","year":"2014","journal-title":"J.\u00a0Hepatol."},{"key":"10.1016\/j.str.2018.07.004_bib17","doi-asserted-by":"crossref","first-page":"6202","DOI":"10.1074\/jbc.M116.772996","article-title":"Unraveling the structural basis of grazoprevir potency against clinically relevant substitutions in hepatitis C virus NS3\/4A protease from genotype 1a","volume":"292","author":"Guo","year":"2017","journal-title":"J.\u00a0Biol. Chem."},{"key":"10.1016\/j.str.2018.07.004_bib18","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1021\/acs.jctc.5b00864","article-title":"OPLS3: a force field providing broad coverage of drug-like small molecules and proteins","volume":"12","author":"Harder","year":"2015","journal-title":"J.\u00a0Chem. Theory Comput."},{"key":"10.1016\/j.str.2018.07.004_bib19","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1021\/ml300017p","article-title":"Discovery of MK-5172, a macrocyclic hepatitis C virus NS3\/4a protease inhibitor","volume":"3","author":"Harper","year":"2012","journal-title":"ACS Med. Chem. Lett."},{"key":"10.1016\/j.str.2018.07.004_bib20","doi-asserted-by":"crossref","first-page":"R121","DOI":"10.1016\/S1359-0278(96)00056-9","article-title":"Double-mutant cycles: a powerful tool for analyzing protein structure and function","volume":"1","author":"Horovitz","year":"1996","journal-title":"Fold. Des."},{"key":"10.1016\/j.str.2018.07.004_bib21","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/S0022-2836(02)00470-9","article-title":"On the role of the crystal environment in determining protein side-chain conformations","volume":"320","author":"Jacobson","year":"2002","journal-title":"J.\u00a0Mol. Biol."},{"key":"10.1016\/j.str.2018.07.004_bib22","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J.\u00a0Chem. Phys."},{"key":"10.1016\/j.str.2018.07.004_bib23","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.jhep.2017.03.039","article-title":"Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1-6 without cirrhosis","volume":"67","author":"Kwo","year":"2017","journal-title":"J.\u00a0Hepatol."},{"key":"10.1016\/j.str.2018.07.004_bib24","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1002\/prot.20784","article-title":"Generalized correlation for biomolecular dynamics","volume":"62","author":"Lange","year":"2006","journal-title":"Proteins"},{"key":"10.1016\/j.str.2018.07.004_bib25","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/S0140-6736(14)61795-5","volume":"385","author":"Lawitz","year":"2014","journal-title":"Lancet"},{"key":"10.1016\/j.str.2018.07.004_bib26","article-title":"Characterization of HCV\u00a0resistance from a 3-day monotherapy study of voxilaprevir, a novel pangenotypic NS3\/4A protease inhibitor","author":"Lawitz","year":"2017","journal-title":"Antivir. Ther."},{"key":"10.1016\/j.str.2018.07.004_bib27","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1128\/AAC.02264-15","article-title":"Potent antiviral activities of the direct-acting antivirals ABT-493 and ABT-530 with three-day monotherapy for hepatitis C virus genotype 1 infection","volume":"60","author":"Lawitz","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"10.1016\/j.str.2018.07.004_bib28","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1006\/abio.1998.3014","article-title":"Use of a fluorescence plate reader for measuring kinetic parameters with inner filter effect correction","volume":"267","author":"Liu","year":"1999","journal-title":"Anal. Biochem."},{"key":"10.1016\/j.str.2018.07.004_bib29","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1002\/hep.27934","article-title":"Hepatitis C\u00a0virus drug resistance-associated substitutions: state of the art summary","volume":"62","author":"Lontok","year":"2015","journal-title":"Hepatology"},{"key":"10.1016\/j.str.2018.07.004_bib30","doi-asserted-by":"crossref","first-page":"5699","DOI":"10.1021\/acs.jmedchem.7b00426","article-title":"Hepatitis c virus NS3\/4A protease inhibitors incorporating flexible P2 quinoxalines target drug resistant viral variants","volume":"60","author":"Matthew","year":"2017","journal-title":"J.\u00a0Med. Chem."},{"key":"10.1016\/j.str.2018.07.004_bib31","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1107\/S0021889807021206","article-title":"Phaser crystallographic software","volume":"40","author":"McCoy","year":"2007","journal-title":"J.\u00a0Appl. Crystallogr."},{"key":"10.1016\/j.str.2018.07.004_bib32","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1002\/hep.27259","article-title":"Global distribution and prevalence of hepatitis C virus genotypes","volume":"61","author":"Messina","year":"2015","journal-title":"Hepatology"},{"key":"10.1016\/j.str.2018.07.004_bib33","article-title":"In\u00a0vitro antiviral activity and resistance profile of the next-generation hepatitis c virus NS3\/4A protease inhibitor glecaprevir","volume":"62","author":"Ng","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"10.1016\/j.str.2018.07.004_bib34","doi-asserted-by":"crossref","first-page":"5673","DOI":"10.1074\/jbc.M112.439455","article-title":"Molecular mechanism by which a potent hepatitis C virus NS3-NS4A protease inhibitor overcomes emergence of resistance","volume":"288","author":"O'Meara","year":"2013","journal-title":"J.\u00a0Biol. Chem."},{"key":"10.1016\/j.str.2018.07.004_bib35","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1021\/ct100578z","article-title":"PROPKA3: consistent treatment of internal and surface residues in empirical pKa predictions","volume":"7","author":"Olsson","year":"2011","journal-title":"J.\u00a0Chem. Theory Comput."},{"key":"10.1016\/j.str.2018.07.004_bib36","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S0076-6879(97)76066-X","article-title":"Processing of X-ray diffraction data collected in oscillation mode","volume":"276","author":"Otwinowski","year":"1997","journal-title":"Methods Enzymol."},{"key":"10.1016\/j.str.2018.07.004_bib37","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1053\/j.gastro.2016.04.003","article-title":"Hepatitis C virus resistance to direct-acting antiviral drugs in interferon-free regimens","volume":"151","author":"Pawlotsky","year":"2016","journal-title":"Gastroenterology"},{"key":"10.1016\/j.str.2018.07.004_bib38","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1128\/AAC.04227-14","article-title":"In\u00a0vitro and in\u00a0vivo antiviral activity and resistance profile of the hepatitis C virus NS3\/4A protease inhibitor ABT-450","volume":"59","author":"Pilot-Matias","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"10.1016\/j.str.2018.07.004_bib39","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1002\/hep.29081","article-title":"Glecaprevir and pibrentasvir for 12\u00a0weeks for hepatitis C virus genotype 1 infection and prior direct-acting antiviral treatment","volume":"66","author":"Poordad","year":"2017","journal-title":"Hepatology"},{"key":"10.1016\/j.str.2018.07.004_bib40","doi-asserted-by":"crossref","first-page":"11956","DOI":"10.1021\/ja504096m","article-title":"Drug resistance conferred by mutations outside the active site through alterations in the dynamic and structural ensemble of HIV-1 protease","volume":"136","author":"Ragland","year":"2014","journal-title":"J.\u00a0Am. Chem. Soc."},{"key":"10.1016\/j.str.2018.07.004_bib41","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1111\/jvh.12527","article-title":"GS-9857 in patients with chronic hepatitis C virus genotype 1-4 infection: a randomized, double-blind, dose-ranging phase 1 study","volume":"23","author":"Rodriguez-Torres","year":"2016","journal-title":"J.\u00a0Viral Hepat."},{"key":"10.1016\/j.str.2018.07.004_bib42","doi-asserted-by":"crossref","first-page":"e1002832","DOI":"10.1371\/journal.ppat.1002832","article-title":"The molecular basis of drug resistance against hepatitis C virus NS3\/4A protease inhibitors","volume":"8","author":"Romano","year":"2012","journal-title":"PLoS Pathog."},{"key":"10.1016\/j.str.2018.07.004_bib43","doi-asserted-by":"crossref","first-page":"20986","DOI":"10.1073\/pnas.1006370107","article-title":"Drug resistance against HCV NS3\/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding","volume":"107","author":"Romano","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"10.1016\/j.str.2018.07.004_bib44","doi-asserted-by":"crossref","first-page":"6106","DOI":"10.1128\/JVI.00377-11","article-title":"Molecular mechanisms of viral and host cell substrate recognition by hepatitis C virus NS3\/4A protease","volume":"85","author":"Romano","year":"2011","journal-title":"J.\u00a0Virol."},{"key":"10.1016\/j.str.2018.07.004_bib45","doi-asserted-by":"crossref","first-page":"30ra32","DOI":"10.1126\/scitranslmed.3000544","article-title":"Rapid emergence of protease inhibitor resistance in hepatitis C virus","volume":"2","author":"Rong","year":"2010","journal-title":"Sci. Transl. Med."},{"key":"10.1016\/j.str.2018.07.004_bib46","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.1021\/jm401507s","article-title":"Discovery and development of simeprevir (TMC435), a HCV NS3\/4A protease inhibitor","volume":"57","author":"Rosenquist","year":"2014","journal-title":"J.\u00a0Med. Chem."},{"key":"10.1016\/j.str.2018.07.004_bib63","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1002\/cmdc.201402558","article-title":"P2-Quinazolinones and bis-macrocycles as new templates for next-generation hepatitis C virus NS3\/4A protease inhibitors: discovery of MK-2748 and MK-6325","volume":"10","author":"Rudd","year":"2015","journal-title":"Chem. Med. Chem."},{"key":"10.1016\/j.str.2018.07.004_bib47","first-page":"404","article-title":"The \u201cmegaprimer\u201d method of site-directed mutagenesis","volume":"8","author":"Sarkar","year":"1990","journal-title":"Biotechniques"},{"key":"10.1016\/j.str.2018.07.004_bib48","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1053\/j.gastro.2009.11.055","article-title":"Resistance to direct antiviral agents in patients with hepatitis C virus infection","volume":"138","author":"Sarrazin","year":"2010","journal-title":"Gastroenterology"},{"key":"10.1016\/j.str.2018.07.004_bib49","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","article-title":"Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments","volume":"27","author":"Sastry","year":"2013","journal-title":"J.\u00a0Comput. Aided Mol. Des."},{"key":"10.1016\/j.str.2018.07.004_bib50","series-title":"The PyMOL Molecular Graphics System, Version 1.8","author":"Schr\u00f6dinger","year":"2015"},{"key":"10.1016\/j.str.2018.07.004_bib51","series-title":"PyMOL Release 2017-4: Prime","author":"Schr\u00f6dinger","year":"2017"},{"key":"10.1016\/j.str.2018.07.004_bib52","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1002\/hep.26744","article-title":"Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and genotype assignment web resource","volume":"59","author":"Smith","year":"2014","journal-title":"Hepatology"},{"key":"10.1016\/j.str.2018.07.004_bib53","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1021\/ct200133y","article-title":"Improved treatment of ligands and coupling effects in empirical calculation and rationalization of pKa values","volume":"7","author":"S\u00f8ndergaard","year":"2011","journal-title":"J.\u00a0Chem. Theory Comput."},{"key":"10.1016\/j.str.2018.07.004_bib54","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1021\/cb5006118","article-title":"Structural analysis of asunaprevir resistance in HCV NS3\/4A protease","volume":"9","author":"Soumana","year":"2014","journal-title":"ACS Chem. Biol."},{"key":"10.1016\/j.str.2018.07.004_bib55","doi-asserted-by":"crossref","first-page":"11850","DOI":"10.1021\/jacs.6b06454","article-title":"Molecular and dynamic mechanism underlying drug resistance in genotype 3 hepatitis C NS3\/4A protease","volume":"138","author":"Soumana","year":"2016","journal-title":"J.\u00a0Am. Chem. Soc."},{"key":"10.1016\/j.str.2018.07.004_bib56","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1021\/acschembio.5b00647","article-title":"Structural and thermodynamic effects of macrocyclization in HCV NS3\/4A inhibitor MK-5172","volume":"11","author":"Soumana","year":"2016","journal-title":"ACS Chem. Biol."},{"key":"10.1016\/j.str.2018.07.004_bib57","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1016\/S0140-6736(14)61793-1","volume":"385","author":"Sulkowski","year":"2015","journal-title":"Lancet"},{"key":"10.1016\/j.str.2018.07.004_bib58","doi-asserted-by":"crossref","first-page":"4161","DOI":"10.1128\/AAC.00324-12","article-title":"MK-5172, a selective inhibitor of hepatitis C virus NS3\/4a protease with broad activity across genotypes and resistant variants","volume":"56","author":"Summa","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"10.1016\/j.str.2018.07.004_bib59","doi-asserted-by":"crossref","first-page":"1990","DOI":"10.1063\/1.463137","article-title":"Reversible multiple time scale molecular dynamics","volume":"97","author":"Tuckerman","year":"1992","journal-title":"J.\u00a0Chem. Phys."},{"key":"10.1016\/j.str.2018.07.004_bib65","first-page":"6995174","article-title":"Hepatitis C virus inhibitors","author":"Wang","year":"2006","journal-title":"US Patent"},{"key":"10.1016\/j.str.2018.07.004_bib60","unstructured":"Wittekind, M., Weinheirner, S., Zhang, Y., and Goldfarb, V. (2002). Modified forms of hepatitis C NS3 protease for facilitating inhibitor screening and structural studies of protease-inhibitor complexes. US patent US20020106642A1, filed September 27, 2001, and Published August 8, 2002."},{"key":"10.1016\/j.str.2018.07.004_bib61","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.tim.2016.03.010","article-title":"Improving viral protease inhibitors to counter drug resistance","volume":"24","author":"Yilmaz","year":"2016","journal-title":"Trends Microbiol."},{"key":"10.1016\/j.str.2018.07.004_bib62","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1056\/NEJMoa1401561","article-title":"Retreatment of HCV with ABT-450\/r-ombitasvir and dasabuvir with ribavirin","volume":"370","author":"Zeuzem","year":"2014","journal-title":"N.\u00a0Engl. J. Med."}],"container-title":["Structure"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0969212618302508?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0969212618302508?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T02:33:27Z","timestamp":1760841207000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0969212618302508"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10]]},"references-count":64,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2018,10]]}},"alternative-id":["S0969212618302508"],"URL":"https:\/\/doi.org\/10.1016\/j.str.2018.07.004","relation":{},"ISSN":["0969-2126"],"issn-type":[{"value":"0969-2126","type":"print"}],"subject":[],"published":{"date-parts":[[2018,10]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Molecular Mechanism of Resistance in a Clinically Significant Double-Mutant Variant of HCV NS3\/4A Protease","name":"articletitle","label":"Article Title"},{"value":"Structure","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.str.2018.07.004","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2018 Elsevier Ltd.","name":"copyright","label":"Copyright"}]}}