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To design and develop effective antiviral therapeutics against DNA viruses, the DNA\u2010dependent RNA polymerase (DdRp) of poxviruses has emerged as a promising drug target. In the present study, we modeled the three\u2010dimensional (3D) structure of DdRp using a template\u2010based homology approach. After modeling, virtual screening was performed to probe the molecular interactions between 1755 Food and Drug Administration\u2010approved small molecule drugs (\u2264500 molecular weight) and the DdRp of Mpox. Based on the binding affinity and molecular interaction patterns, five drugs, lumacaftor (\u221211.7\u2009kcal\/mol), conivaptan (\u221211.7\u2009kcal\/mol), betulinic acid (\u221211.6\u2009kcal\/mol), fluspirilene (\u221211.3\u2009kcal\/mol), and imatinib (\u221211.2\u2009kcal\/mol), have been ranked as the top drug compounds interacting with Mpox DdRp. Complexes of these shortlisted drugs with DdRp were further evaluated using state\u2010of\u2010the\u2010art all\u2010atoms molecular dynamics (MD) simulations on 200 nanoseconds followed by principal component analysis (PCA). MD simulations and PCA results revealed highly stable interactions of these small drugs with DdRp. After due validation in wet\u2010lab using available in vitro and in vivo experiments, these repurposed drugs can be further utilized for the treatment of contagious Mpox virus. The outcome of this study may establish a solid foundation to screen repurposed and natural compounds as potential antiviral therapeutics against different highly pathogenic viruses.<\/jats:p>","DOI":"10.1002\/jcb.30397","type":"journal-article","created":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T11:29:55Z","timestamp":1679484595000},"page":"701-715","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Drug repurposing for Mpox: Discovery of small molecules as potential inhibitors against DNA\u2010dependent RNA polymerase using molecular modeling approach"],"prefix":"10.1002","volume":"124","author":[{"given":"Mansi","family":"Dutt","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Department of Paediatrics, IWK Health Center, Canadian Centre for Vaccinology (CCfV), Faculty of Medicine Dalhousie University Halifax Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5023-7618","authenticated-orcid":false,"given":"Anuj","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Department of Paediatrics, IWK Health Center, Canadian Centre for Vaccinology (CCfV), Faculty of Medicine Dalhousie University Halifax Canada"},{"name":"European Virus Bioinformatics Center Jena Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madhusmita","family":"Rout","sequence":"additional","affiliation":[{"name":"Bioinformatics Division ICMR\u2010Regional Medical Research Centre Bhubaneswar Odisha India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9726-8454","authenticated-orcid":false,"given":"Budheswar","family":"Dehury","sequence":"additional","affiliation":[{"name":"Bioinformatics Division ICMR\u2010Regional Medical Research Centre Bhubaneswar Odisha India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gustavo","family":"Martinez","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Department of Paediatrics, IWK Health Center, Canadian Centre for Vaccinology (CCfV), Faculty of Medicine Dalhousie University Halifax Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pacifique","family":"Ndishimye","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Department of Paediatrics, IWK Health Center, Canadian Centre for Vaccinology (CCfV), Faculty of Medicine Dalhousie University Halifax Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alyson A.","family":"Kelvin","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Disease Organization (VIDO) University of Saskatchewan Saskatoon Saskatchewan Canada"},{"name":"Department of Biochemistry, Microbiology, and Immunology University of Saskatchewan Saskatoon Saskatchewan Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J.","family":"Kelvin","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Department of Paediatrics, IWK Health Center, Canadian Centre for Vaccinology (CCfV), Faculty of Medicine Dalhousie University Halifax Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,3,22]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1080\/22221751.2022.2095309"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/v13010043"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/v12111257"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-022-00776-z"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01907-y"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.81215-0"},{"key":"e_1_2_9_8_1","unstructured":"Monkeypox: experts give virus variants new names. 2023. 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