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The NS5B polymerase holds special significance as the target of intervention against HCV infection. The current study kindles benzothiazine derivatives against HCV NS5B polymerase through in silico and experimental approaches. Following docking, the compound 2\u2010(3,4\u2010dimethyl\u20105,5\u2010dioxidobenzo[<jats:italic>e<\/jats:italic>]pyrazolo[4,3\u2010<jats:italic>c<\/jats:italic>][1,2]thiazin\u20102(4<jats:italic>H<\/jats:italic>)\u2010yl)\u2010<jats:italic>N<\/jats:italic>\u2010(2\u2010fluorobenzyl)acetamide was revealed to form effective binding interaction in the proposed site of HCV NS5B with a score of \u221210\u00a0kcal\/mol and subsequently was deciphered through molecular dynamics (MD) simulation study which indicated interaction of residues TYR_382, VAL_381 and HIS_467 through hydrophobic interaction and two residues such as GLU_202 and LYS_209 contributed in the formation of water bridges. The subsequent in silico pharmacological analysis revealed its safe drug profile. The cytotoxicity activity of compound 6c indicated to be non\u2010toxic in HepG2 cells at concentration ranges from 0.001\u20131.0\u00a0\u00b5mol\/L with &gt;80% cell viability and diminished expression of the HCV NS5B to 98% at the dose of 1.0\u00a0\u00b5mol\/L and 90% at 0.5\u00b5mol\/L. Thus the hit compound 6c might be a potent NS5B polymerase inhibitor required to be validated further through <jats:italic>in vivo<\/jats:italic> and preclinical studies.<\/jats:p>","DOI":"10.1111\/1440-1681.13571","type":"journal-article","created":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T04:07:00Z","timestamp":1628827620000},"page":"1653-1661","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Discovery of Novel HCV NS5B polymerase inhibitor,\u00a02\u2010(3,4\u2010dimethyl\u20105,5\u2010dioxidobenzo[<i>e<\/i>]pyrazolo[4,3\u2010<i>c<\/i>][1,2]thiazin\u20102(4<i>H<\/i>)\u2010yl)\u2010<i>N<\/i>\u2010(2\u2010fluorobenzyl)acetamide via molecular docking and experimental approach"],"prefix":"10.1111","volume":"48","author":[{"given":"Hina","family":"Khalid","sequence":"first","affiliation":[{"name":"Department of Bioinformatics and Biotechnology Government College University Faisalabad (GCUF) Faisalabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sana","family":"Shahid","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Biotechnology Government College University Faisalabad (GCUF) Faisalabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Somayya","family":"Tariq","sequence":"additional","affiliation":[{"name":"Center of Excellence in Molecular Biology University of the Punjab Lahore Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bushra","family":"Ijaz","sequence":"additional","affiliation":[{"name":"Center of Excellence in Molecular Biology University of the Punjab Lahore Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5495-805X","authenticated-orcid":false,"given":"Usman Ali","family":"Ashfaq","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Biotechnology Government College University Faisalabad (GCUF) Faisalabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matloob","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Department of Chemistry Government College University Faisalabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,9,6]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1258\/095646204322637182"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0251934"},{"key":"e_1_2_8_4_1","doi-asserted-by":"crossref","unstructured":"PonzianiFR GasbarriniA PompiliM BurraP FagiuoliS.Management of hepatitis C virus infection recurrence after liver transplantation: an overview. 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