{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:33:56Z","timestamp":1791920036570,"version":"4.3.4"},"reference-count":47,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,9,30]],"date-time":"2022-09-30T00:00:00Z","timestamp":1664496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The World Health Organization declared monkeypox a global public health emergency on 23 July 2022. This disease was caused by the monkeypox virus (MPXV), which was first identified in 1958 in Denmark. The MPXV is a member of the Poxviridae family, the Chordopoxvirinae subfamily, and the genus Orthopoxvirus, which share high similarities with the vaccinia virus (the virus used to produce the smallpox vaccine). For the initial stage of infection, the MPXV needs to attach to the human cell surface glycosaminoglycan (GAG) adhesion molecules using its E8 protein. However, up until now, neither a structure for the MPXV E8 protein nor a specific cure for the MPXV exists. This study aimed to search for small molecules that inhibit the MPXV E8 protein, using computational approaches. In this study, a high-quality three-dimensional structure of the MPXV E8 protein was retrieved by homology modeling using the AlphaFold deep learning server. Subsequent molecular docking and molecular dynamics simulations (MDs) for a cumulative duration of 2.1 microseconds revealed that ZINC003977803 (Diosmin) and ZINC008215434 (Flavin adenine dinucleotide-FAD) could be potential inhibitors against the E8 protein with the MM\/GBSA binding free energies of \u221238.19 \u00b1 9.69 and \u221235.59 \u00b1 7.65 kcal\u00b7mol\u22121, respectively.<\/jats:p>","DOI":"10.3390\/ijms231911570","type":"journal-article","created":{"date-parts":[[2022,10,8]],"date-time":"2022-10-08T22:19:27Z","timestamp":1665267567000},"page":"11570","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Identification of Diosmin and Flavin Adenine Dinucleotide as Repurposing Treatments for Monkeypox Virus: A Computational Study"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8149-9952","authenticated-orcid":false,"given":"Thua-Phong","family":"Lam","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viet-Hung","family":"Tran","sequence":"additional","affiliation":[{"name":"Institute of Drug Quality Control Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7313-9853","authenticated-orcid":false,"given":"Tan Thanh","family":"Mai","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nghia Vo-Trong","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bao-Tran Ngoc","family":"Dang","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minh-Tri","family":"Le","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam"},{"name":"School of Medicine, Vietnam National University, Ho Chi Minh City 700000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thanh-Dao","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3886-3210","authenticated-orcid":false,"given":"Dieu-Thuong Thi","family":"Trinh","sequence":"additional","affiliation":[{"name":"Faculty of Traditional Medicine, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5279-9614","authenticated-orcid":false,"given":"Khac-Minh","family":"Thai","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1001\/jama.2022.12513","article-title":"The WHO Declaration of Monkeypox as a Global Public Health Emergency","volume":"328","author":"Nuzzo","year":"2022","journal-title":"JAMA"},{"key":"ref_2","unstructured":"World Health Organization (2022, September 08). Multi-Country Outbreak of Monkeypox, External Situation Report #5\u20137 September 2022. Available online: https:\/\/www.who.int\/publications\/m\/item\/multi-country-outbreak-of-monkeypox-external-situation-report-5\u20137-September-2022."},{"key":"ref_3","unstructured":"World Health Organization (2022, September 08). Monkeypox. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/monkeypox."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"ofac310","DOI":"10.1093\/ofid\/ofac310","article-title":"Monkeypox: A Contemporary Review for Healthcare Professionals","volume":"9","author":"Titanji","year":"2022","journal-title":"Open Forum Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2915","DOI":"10.1099\/0022-1317-83-12-2915","article-title":"The formation and function of extracellular enveloped vaccinia virus","volume":"83","author":"Smith","year":"2002","journal-title":"J. Gen. Virol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.virs.2022.07.006","article-title":"Monkeypox virus: A re-emergent threat to humans","volume":"37","author":"Gong","year":"2022","journal-title":"Virol. Sin."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"18572","DOI":"10.1073\/pnas.0509239102","article-title":"Poxvirus multiprotein entry\u2013fusion complex","volume":"102","author":"Senkevich","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1099\/vir.0.80831-0","article-title":"Entry of the vaccinia virus intracellular mature virion and its interactions with glycosaminoglycans","volume":"86","author":"Carter","year":"2005","journal-title":"J. Gen. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3353","DOI":"10.1128\/JVI.74.7.3353-3365.2000","article-title":"Vaccinia virus envelope H3L protein binds to cell surface heparan sulfate and is important for intracellular mature virion morphogenesis and virus infection in vitro and in vivo","volume":"74","author":"Lin","year":"2000","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1128\/JVI.72.2.1577-1585.1998","article-title":"A27L protein mediates vaccinia virus interaction with cell surface heparan sulfate","volume":"72","author":"Chung","year":"1998","journal-title":"J. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"8750","DOI":"10.1128\/JVI.73.10.8750-8761.1999","article-title":"Vaccinia virus envelope D8L protein binds to cell surface chondroitin sulfate and mediates the adsorption of intracellular mature virions to cells","volume":"73","author":"Hsiao","year":"1999","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e5","DOI":"10.1017\/S1462399409001367","article-title":"Proteoglycans in host-pathogen interactions: Molecular mechanisms and therapeutic implications","volume":"12","author":"Bartlett","year":"2010","journal-title":"Expert Rev. Mol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8050","DOI":"10.1128\/JVI.00836-12","article-title":"Structural and biochemical characterization of the vaccinia virus envelope protein D8 and its recognition by the antibody LA5","volume":"86","author":"Matho","year":"2012","journal-title":"J. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Matho, M.H., de Val, N., Miller, G.M., Brown, J., Schlossman, A., Meng, X., Crotty, S., Peters, B., Xiang, Y., and Hsieh-Wilson, L.C. (2014). Murine Anti-vaccinia Virus D8 Antibodies Target Different Epitopes and Differ in Their Ability to Block D8 Binding to CS-E. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004495"},{"key":"ref_15","unstructured":"FDA (2022, July 29). Smallpox Preparedness and Response Updates from FDA, Available online: https:\/\/www.fda.gov\/emergency-preparedness-and-response\/mcm-issues\/smallpox-preparedness-and-response-updates-fda."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"276","DOI":"10.4103\/tcmj.tcmj_318_21","article-title":"Computer-aided discovery, design, and investigation of COVID-19 therapeutics","volume":"34","author":"Chang","year":"2022","journal-title":"Tzu Chi Med. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/j.jsps.2022.03.002","article-title":"The pill of recovery; Molnupiravir for treatment of COVID-19 patients; a systematic review","volume":"30","author":"Kamal","year":"2022","journal-title":"Saudi Pharm. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3381","DOI":"10.1093\/nar\/gkg520","article-title":"SWISS-MODEL: An automated protein homology-modeling server","volume":"31","author":"Schwede","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"456","DOI":"10.2174\/1389203715666140327114232","article-title":"A review of methods available to estimate solvent-accessible surface areas of soluble proteins in the folded and unfolded states","volume":"15","author":"Ali","year":"2014","journal-title":"Curr. Protein Pept. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/bs.apcsb.2015.09.004","article-title":"Molecular Dynamics: New Frontier in Personalized Medicine","volume":"102","author":"Sneha","year":"2016","journal-title":"Adv. Protein Chem. Struct. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/nrd1468","article-title":"Drug repositioning: Identifying and developing new uses for existing drugs","volume":"3","author":"Ashburn","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"591","DOI":"10.2147\/VHRM.S324112","article-title":"Is There a Difference in the Clinical Efficacy of Diosmin and Micronized Purified Flavonoid Fraction for the Treatment of Chronic Venous Disorders? Review of Available Evidence","volume":"17","author":"Cazaubon","year":"2021","journal-title":"Vasc. Health Risk Manag."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Huwait, E., and Mobashir, M. (2022). Potential and Therapeutic Roles of Diosmin in Human Diseases. Biomedicines, 10.","DOI":"10.3390\/biomedicines10051076"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s11101-021-09759-z","article-title":"Flavonoids are promising safe therapy against COVID-19","volume":"21","author":"Alzaabi","year":"2022","journal-title":"Phytochem. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.ymeth.2021.02.017","article-title":"Multi-targeting approach for nsp3, nsp9, nsp12 and nsp15 proteins of SARS-CoV-2 by Diosmin as illustrated by molecular docking and molecular dynamics simulation methodologies","volume":"195","author":"Kumar","year":"2021","journal-title":"Methods"},{"key":"ref_26","first-page":"968","article-title":"Stimulation of antiviral activities of interferon by a liver extract preparation","volume":"47","author":"Yokochi","year":"1997","journal-title":"Arzneimittelforschung"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s11655-020-3427-6","article-title":"In Silico Screening of Potential Spike Glycoprotein Inhibitors of SARS-CoV-2 with Drug Repurposing Strategy","volume":"26","author":"Wei","year":"2020","journal-title":"Chin. J. Integr. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/j.apsb.2020.02.008","article-title":"Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods","volume":"10","author":"Wu","year":"2020","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"105049","DOI":"10.1016\/j.compbiomed.2021.105049","article-title":"Combined deep learning and molecular docking simulations approach identifies potentially effective FDA approved drugs for repurposing against SARS-CoV-2","volume":"141","author":"Anwaar","year":"2022","journal-title":"Comput. Biol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Huang, F., Zhang, C., Liu, Q., Zhao, Y., Zhang, Y., Qin, Y., Li, X., Li, C., Zhou, C., and Jin, N. (2020). Identification of amitriptyline HCl, flavin adenine dinucleotide, azacitidine and calcitriol as repurposing drugs for influenza A H5N1 virus-induced lung injury. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008341"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6065","DOI":"10.1021\/acs.jcim.0c00675","article-title":"ZINC20\u2014A free ultralarge-scale chemical database for ligand discovery","volume":"60","author":"Irwin","year":"2020","journal-title":"J. Chem. Inf. Model."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1758-2946-3-33","article-title":"Open Babel: An open chemical toolbox","volume":"3","author":"Banck","year":"2011","journal-title":"J. Cheminform."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.jmb.2008.07.038","article-title":"The Crystal and Molecular Structures of a Cathepsin K:Chondroitin Sulfate Complex","volume":"383","author":"Li","year":"2008","journal-title":"J. Mol. Biol."},{"key":"ref_36","unstructured":"(PyMOL, 2020). PyMOL, Version 2.5.2."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"W530","DOI":"10.1093\/nar\/gkab294","article-title":"PLIP 2021: Expanding the scope of the protein\u2013ligand interaction profiler to DNA and RNA","volume":"49","author":"Adasme","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.1002\/jcc.21816","article-title":"SwissParam: A fast force field generation tool for small organic molecules","volume":"32","author":"Zoete","year":"2011","journal-title":"J. Comput. Chem."},{"key":"ref_41","first-page":"5068","article-title":"From Proteins to Perturbed Hamiltonians: A Suite of Tutorials for the GROMACS-2018 Molecular Simulation Package [Article v1.0]","volume":"1","author":"Lemkul","year":"2018","journal-title":"LiveCoMS"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"014101","DOI":"10.1063\/1.2408420","article-title":"Canonical sampling through velocity rescaling","volume":"126","author":"Bussi","year":"2007","journal-title":"J. Chem. Phys."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"7182","DOI":"10.1063\/1.328693","article-title":"Polymorphic transitions in single crystals: A new molecular dynamics method","volume":"52","author":"Parrinello","year":"1981","journal-title":"J. Appl. Phys."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual molecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph. Model."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Tran, Q.-H., Nguyen, Q.-T., Vo, N.-Q.-H., Mai, T.T., Tran, T.-T.-N., Tran, T.-D., Le, M.-T., Trinh, D.-T.T., and Thai, K.-M. (2022). Structure-based 3D-Pharmacophore modeling to discover novel interleukin 6 inhibitors: An in silico screening, molecular dynamics simulations and binding free energy calculations. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0266632"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6281","DOI":"10.1021\/acs.jctc.1c00645","article-title":"gmx_MMPBSA: A new tool to perform end-state free energy calculations with GROMACS","volume":"17","author":"Valiente","year":"2021","journal-title":"J. Chem. Theory Comput."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1002\/prot.20033","article-title":"Exploring protein native states and large-scale conformational changes with a modified generalized born model","volume":"55","author":"Onufriev","year":"2004","journal-title":"Proteins Struct. Funct. Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/19\/11570\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:44:24Z","timestamp":1760143464000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/19\/11570"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,30]]},"references-count":47,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["ijms231911570"],"URL":"https:\/\/doi.org\/10.3390\/ijms231911570","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,30]]}}}