{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T02:54:53Z","timestamp":1792637693475,"version":"4.5.0"},"reference-count":144,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T00:00:00Z","timestamp":1615507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Chem."],"abstract":"<jats:p>\n                    The Coronavirus disease-19 (COVID-19) pandemic is still devastating the world causing significant social, economic, and political chaos. Corresponding to the absence of globally approved antiviral drugs for treatment and vaccines for controlling the pandemic, the number of cases and\/or mortalities are still rising. Current patient management relies on supportive treatment and the use of repurposed drugs as an indispensable option. Of a crucial role in the viral life cycle, ongoing studies are looking for potential inhibitors to the main protease (M\n                    <jats:sup>pro<\/jats:sup>\n                    ) of severe acute respiratory syndrome Coronavirus -2 (SARS-CoV-2) to tackle the pandemic. Although promising results have been achieved in searching for drugs inhibiting the M\n                    <jats:sup>pro<\/jats:sup>\n                    , work remains to be done on designing structure-based improved drugs. This review discusses the structural basis of potential inhibitors targeting SARS-CoV-2 M\n                    <jats:sup>pro<\/jats:sup>\n                    , identifies gaps, and provides future directions. Further, compounds with potential M\n                    <jats:sup>pro<\/jats:sup>\n                    based antiviral activity are highlighted.\n                  <\/jats:p>","DOI":"10.3389\/fchem.2021.622898","type":"journal-article","created":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T00:42:20Z","timestamp":1615509740000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":277,"title":["Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease"],"prefix":"10.3389","volume":"9","author":[{"given":"Hylemariam Mihiretie","family":"Mengist","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tebelay","family":"Dilnessa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tengchuan","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"590263","DOI":"10.3389\/fchem.2020.590263","article-title":"Computational prediction of potential inhibitors of the main protease of SARS-CoV-2","volume":"8","author":"Abel","year":"2020","journal-title":"Front. Chem."},{"key":"B2","doi-asserted-by":"crossref","first-page":"173664","DOI":"10.1016\/j.ejphar.2020.173664","article-title":"Screening Malaria-box compounds to identify potential inhibitors against SARS-CoV-2 Mpro using molecular docking and dynamics simulations studies","volume":"890","author":"Ahamad","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"115860","DOI":"10.1016\/j.bmc.2020.115860","article-title":"Protease targeted COVID-19 drug discovery and its challenges: insight into viral main protease (Mpro) and papain-like protease (PLpro) inhibitors","volume":"20","author":"Amin","year":"2020","journal-title":"Bioorg. Med. Chem."},{"key":"B4","doi-asserted-by":"publisher","first-page":"3213","DOI":"10.1093\/emboj\/cdf327","article-title":"Structure of coronavirus main proteinase reveals combination of a chymotrypsin fold with an extra alpha-helical domain","volume":"21","author":"Anand","year":"2002","journal-title":"EMBO J."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1763","DOI":"10.1126\/science.1085658","article-title":"Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs","volume":"300","author":"Anand","year":"2003","journal-title":"Science"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1207","DOI":"10.1021\/acscatal.6b03096","article-title":"Computational study of the catalytic mechanism of the cruzain cysteine protease","volume":"7","author":"Arafet","year":"2017","journal-title":"ACS Catal."},{"key":"B7","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.arcmed.2020.09.013","volume":"52","author":"Baby","year":"2020","journal-title":"Targeting SARS-CoV-2 main protease: a computational drug repurposing studyArchives Medical Res."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.26434\/chemrxiv.12153615","article-title":"Structural similarity of SARS-CoV2 Mpro and HCV NS3\/4A proteases suggests new approaches for identifying existing drugs useful as COVID-19 therapeutics","author":"Bafna","year":"2020","journal-title":"ChemRxiv"},{"key":"B9","doi-asserted-by":"publisher","first-page":"40264","DOI":"10.1039\/D0RA90120B","article-title":"Correction: pharmacophore-based approaches in the rational repurposing technique for FDA approved drugs targeting SARS-CoV-2 Mpro","volume":"10","author":"Balaramnavar","year":"2020","journal-title":"RSC Adv."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/07391102.2020.1850359","article-title":"Synthetic flavonoids as potential antiviral agents against SARS-CoV-2 main protease","author":"Batool","year":"2020","journal-title":"J. Biomol. Struct. Dyn."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1813","DOI":"10.1056\/NEJMoa2007764","article-title":"Remdesivir for the treatment of Covid-19","volume":"383","author":"Beigel","year":"2020","journal-title":"New Engl. J. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1128\/AAC.49.2.619-626.2005","article-title":"Conservation of amino acids in human rhinovirus 3C protease correlates with broad-spectrum antiviral activity of rupintrivir, a novel human rhinovirus 3C protease inhibitor","volume":"49","author":"Binford","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1787","DOI":"10.1056\/NEJMoa2001282","article-title":"A trial of lopinavir\u2013ritonavir in adults hospitalized with severe Covid-19","volume":"382","author":"Cao","year":"2020","journal-title":"New Engl. J. Med."},{"key":"B14","volume-title":"Features, evaluation and treatment coronavirus (COVID-19)","author":"Cascella","year":"2020"},{"key":"B15","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1039\/D0MO00057D","article-title":"Repurposing drugs against the main protease of SARS-CoV-2: mechanism-based insights supported by available laboratory and clinical data","volume":"16","author":"Chakraborti","year":"2020","journal-title":"Mol. Omics"},{"key":"B16","doi-asserted-by":"publisher","first-page":"7095","DOI":"10.1128\/JVI.79.11.7095-7103.2005","article-title":"Cinanserin is an inhibitor of the 3C-like proteinase of severe acute respiratory syndrome coronavirus and strongly reduces virus replication in vitro","volume":"79","author":"Chen","year":"2005","journal-title":"J. Virol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1016\/S0140-6736(20)30211-7","article-title":"Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study","volume":"395","author":"Chen","year":"","journal-title":"The lancet"},{"key":"B18","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1002\/jmv.25681","article-title":"Emerging coronaviruses: genome structure, replication, and pathogenesis","volume":"92","author":"Chen","year":"","journal-title":"J. Med. Virol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"e0240653","DOI":"10.1371\/journal.pone.0240653","article-title":"Potential bioactive glycosylated flavonoids as SARS-CoV-2 main protease inhibitors: a molecular docking and simulation studies","volume":"15","author":"Cherrak","year":"2020","journal-title":"PLoS One"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1080\/07391102.2020.1784289","article-title":"In-silico investigation of phytochemicals from Asparagus racemosus as plausible antiviral agent in COVID-19","author":"Chikhale","year":"2020","journal-title":"J. Biomol. Struct. Dyn."},{"key":"B21","doi-asserted-by":"publisher","first-page":"14958","DOI":"10.1021\/bi0490237","article-title":"Quaternary structure of the severe acute respiratory syndrome (SARS) coronavirus main protease","volume":"43","author":"Chou","year":"2004","journal-title":"Biochemistry"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1080\/07391102.2020.1771424","article-title":"Fragment tailoring strategy to design novel chemical entities as potential binders of novel corona virus main protease","author":"Choudhury","year":"2020","journal-title":"J. Biomol. Struct. Dyn."},{"key":"B23","doi-asserted-by":"publisher","first-page":"382","DOI":"10.15585\/mmwr.mm6913e2","article-title":"Preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019\u2014United States, February 12\u2013March 28, 2020","volume":"69","author":"Chow","year":"2020","journal-title":"Morbidity Mortality Weekly Rep."},{"key":"B24","doi-asserted-by":"publisher","first-page":"e0240079","DOI":"10.1371\/journal.pone.0240079","article-title":"Biochemical screening for SARS-CoV-2 main protease inhibitors","volume":"15","author":"Coelho","year":"2020","journal-title":"PLoS One"},{"key":"B25","first-page":"357","article-title":"\u201cEvolutionary multi-ojective design of SARS-CoV-2 protease inhibitor candidates,\u201d in International conference on parallel problem solving from nature. Cham: Springer","author":"Cofala","year":"2020"},{"key":"B26","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1211\/PJ.2020.2020794","article-title":"Targeting COVID-19: the drugs being fast-tracked through clinical trials and how they work","volume":"304","author":"Connelly","year":"2020","journal-title":"Pharm. J."},{"key":"B27","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/s0083-6729(00)58024-8","article-title":"Structure-based inhibitor design","volume":"58","author":"Craig","year":"2000","journal-title":"Vitam Horm."},{"key":"B28","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/s41579-018-0118-9","article-title":"Origin and evolution of pathogenic coronaviruses","volume":"17","author":"Cui","year":"2019","journal-title":"Nat. Rev. Microbiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.1016\/j.chempr.2020.04.023","article-title":"Chemistry and biology of SARS-CoV-2","volume":"6","author":"D\u00f6mling","year":"2020","journal-title":"Chem"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1126\/science.abb4489","article-title":"Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease","volume":"368","author":"Dai","year":"2020","journal-title":"Science"},{"key":"B31","doi-asserted-by":"publisher","first-page":"Doc08","DOI":"10.3205\/id000034","article-title":"Protease inhibitors for the treatment of hepatitis C virus infection","volume":"5","author":"de Leuw","year":"2017","journal-title":"GMS Infect Dis."},{"key":"B32","doi-asserted-by":"publisher","first-page":"5047","DOI":"10.1038\/s41467-020-18709-w","article-title":"Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease","volume":"11","author":"Douangamath","year":"2020","journal-title":"Nat. Commun."},{"key":"B33","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1038\/nrd3053","article-title":"Emerging principles in protease-based drug discovery","volume":"9","author":"Drag","year":"2010","journal-title":"Nat. Rev. Drug Discov."},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1101\/2020.09.09.287987","article-title":"Near-physiological-temperature serial femtosecond X-ray crystallography reveals novel conformations of SARS-CoV-2 main protease active site for improved drug repurposing","author":"Durdagi","year":"2020","journal-title":"bioRxiv"},{"key":"B35","doi-asserted-by":"publisher","first-page":"38128","DOI":"10.1039\/d0ra04876c","article-title":"Anti-inflammatory, antiallergic and COVID-19 protease inhibitory activities of phytochemicals from the Jordanian hawksbeard: identification, structure\u2013activity relationships, molecular modeling and impact on its folk medicinal uses","volume":"10","author":"Ebada","year":"2020","journal-title":"RSC Adv."},{"key":"B36","doi-asserted-by":"publisher","first-page":"5048","DOI":"10.1038\/s41467-020-18710-3","article-title":"Many small steps towards a COVID-19 drug","volume":"11","author":"Erlanson","year":"2020","journal-title":"Nat. Commun."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1637","DOI":"10.1074\/jbc.M310875200","article-title":"Biosynthesis, purification, and substrate specificity of severe acute respiratory syndrome coronavirus 3C-like proteinase","volume":"279","author":"Fan","year":"2004","journal-title":"J. Biol. Chem."},{"key":"B38","first-page":"1","volume-title":"Coronaviruses: an overview of their replication and pathogenesis","author":"Fehr","year":"2015"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1815","DOI":"10.4155\/fmc-2020-0165","article-title":"Ligand and structure-based virtual screening applied to the SARS-CoV-2 main protease: an in silico repurposing study","volume":"12","author":"Ferraz","year":"2020","journal-title":"Future Med. Chem."},{"key":"B40","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1039\/d0md00282h","article-title":"Identification of LASSBio-1945 as an inhibitor of SARS-CoV-2 main protease (M PRO) through in silico screening supported by molecular docking and a fragment-based pharmacophore model","volume":"12","author":"Franco","year":"2020","journal-title":"RSC Med. Chem."},{"key":"B41","doi-asserted-by":"publisher","first-page":"4417","DOI":"10.1038\/s41467-020-18233-x","article-title":"Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease","volume":"11","author":"Fu","year":"2020","journal-title":"Nat. Commun."},{"key":"B42","doi-asserted-by":"publisher","first-page":"7267","DOI":"10.1021\/acs.jpclett.0c01894","article-title":"Repurposing low-molecular-weight drugs against the main protease of severe acute respiratory syndrome coronavirus 2","volume":"11","author":"Gao","year":"2020","journal-title":"J. Phys. Chem. Lett."},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.26434\/chemrxiv.12673436","article-title":"Copper(II) inhibition of the SARS-CoV-2 main protease","author":"Garza-Lopez","year":"2020","journal-title":"ChemRxiv. Preprint"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1677","DOI":"10.1056\/NEJMp2003762","article-title":"Responding to Covid-19\u2014a once-in-a-century pandemic?","volume":"382","author":"Gates","year":"2020","journal-title":"New Engl. J. Med."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1164\/rccm.202003-0817LE","article-title":"COVID-19 does not lead to a \"typical\" acute respiratory distress syndrome","volume":"201","author":"Gattinoni","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B46","doi-asserted-by":"publisher","first-page":"225","DOI":"10.3390\/md18040225","article-title":"Putative inhibitors of SARS-CoV-2 main protease from a library of marine natural products: a virtual screening and molecular modeling study","volume":"18","author":"Gentile","year":"2020","journal-title":"Mar. Drugs"},{"key":"B47","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1038\/s41564-020-0695-z","article-title":"The species severe acute respiratory syndrome related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2","volume":"5","author":"Gorbalenya","year":"2020","journal-title":"Nat. Microbiol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"4847","DOI":"10.1093\/nar\/17.12.4847","article-title":"Coronavirus genome: prediction of putative functional domains in the non-structural polyprotein by comparative amino acid sequence analysis","volume":"17","author":"Gorbalenya","year":"1989","journal-title":"Nucleic Acids Res."},{"key":"B49","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1038\/s41586-020-2286-9","article-title":"A SARS-CoV-2 protein interaction map reveals targets for drug repurposing","volume":"583","author":"Gordon","year":"2020","journal-title":"Nature"},{"key":"B50","doi-asserted-by":"publisher","first-page":"107575","DOI":"10.1016\/j.jsb.2020.107575","article-title":"SARS-CoV and SARS-CoV-2 main protease residue interaction networks change when bound to inhibitor N3","volume":"211","author":"Griffin","year":"2020","journal-title":"J. Struct. Biol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"5346","DOI":"10.3390\/ijms21155346","article-title":"Computational studies of SARS-CoV-2 3CLpro: insights from MD simulations","volume":"21","author":"Grottesi","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B52","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.virusres.2007.02.015","article-title":"Evaluating the 3C-like protease activity of SARS-Coronavirus: recommendations for standardized assays for drug discovery","volume":"133","author":"Grum-Tokars","year":"2008","journal-title":"Virus Res."},{"key":"B53","doi-asserted-by":"publisher","first-page":"3907","DOI":"10.1128\/aac.47.12.3907-3916.2003","article-title":"Phase II, randomized, double-blind, placebo-controlled studies of ruprintrivir nasal spray 2-percent suspension for prevention and treatment of experimentally induced rhinovirus colds in healthy volunteers","volume":"47","author":"Hayden","year":"2003","journal-title":"Antimicrob. Agents Chemother."},{"key":"B54","doi-asserted-by":"publisher","first-page":"4085","DOI":"10.1111\/febs.12936","article-title":"From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design","volume":"281","author":"Hilgenfeld","year":"2014","journal-title":"FEBS J."},{"key":"B55","first-page":"1075","article-title":"Coronaviridae: the viruses and their replication","volume":"1","author":"Holmes","year":"1996","journal-title":"Fields Virol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"31257","DOI":"10.1074\/jbc.M502577200","article-title":"Mechanism of the maturation process of SARS-CoV 3CL protease","volume":"280","author":"Hsu","year":"2005","journal-title":"J. Biol. Chem."},{"key":"B57","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China","volume":"395","author":"Huang","year":"2020","journal-title":"The lancet"},{"key":"B58","doi-asserted-by":"publisher","first-page":"2487","DOI":"10.1007\/s11224-020-01605-w","article-title":"Repurposing metocurine as main protease inhibitor to develop novel antiviral therapy for COVID-19","volume":"36","author":"Jain","year":"2020","journal-title":"Struct. Chem."},{"key":"B59","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/s41586-020-2223-y","article-title":"Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors","volume":"582","author":"Jin","year":"","journal-title":"Nature"},{"key":"B60","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1038\/s41594-020-0440-6","article-title":"Structural basis for the inhibition of SARS-CoV-2 main protease by antineoplastic drug carmofur","volume":"27","author":"Jin","year":"","journal-title":"Nat. Struct. Mol. Biol."},{"key":"B61","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1007\/s11030-020-10130-1","article-title":"Identification of potential Mpro inhibitors for the treatment of COVID-19 by using systematic virtual screening approach","volume":"25","author":"Kanhed","year":"2020","journal-title":"Mol. Divers."},{"key":"B62","doi-asserted-by":"publisher","first-page":"100484","DOI":"10.1016\/j.imu.2020.100484","article-title":"Plausible mechanisms explaining the role of cucurbitacins as potential therapeutic drugs against coronavirus 2019","volume":"21","author":"Kapoor","year":"2020","journal-title":"Informatics in medicine unlocked"},{"key":"B63","doi-asserted-by":"publisher","first-page":"7983","DOI":"10.1021\/ja00047a004","article-title":"Attack of zwitterionic ammonium thiolates on a distorted anilide as a model for the acylation of papain by amides. A simple demonstration of a bell-shaped pH\/rate profile","volume":"114","author":"Keillor","year":"1992","journal-title":"J. Am. Chem. Soc."},{"key":"B64","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1016\/S0140-6736(17)31791-9","article-title":"Safety and efficacy of ebselen for the prevention of noise-induced hearing loss: a randomised, double-blind, placebo-controlled, phase 2 trial","volume":"390","author":"Kil","year":"2017","journal-title":"Lancet"},{"key":"B65","doi-asserted-by":"publisher","first-page":"e1005531","DOI":"10.1371\/journal.ppat.1005531","article-title":"Reversal of the progression of fatal coronavirus infection in cats by a broad-spectrum coronavirus protease inhibitor","volume":"12","author":"Kim","year":"2016","journal-title":"PLoS Pathog."},{"key":"B66","doi-asserted-by":"publisher","first-page":"11754","DOI":"10.1128\/JVI.01348-12","article-title":"Broad-spectrum antivirals against 3C or 3C-like proteases of picornaviruses, noroviruses, and coronaviruses","volume":"86","author":"Kim","year":"2012","journal-title":"J. Virol."},{"key":"B67","doi-asserted-by":"publisher","first-page":"4942","DOI":"10.1128\/JVI.03688-14","article-title":"Broad-spectrum inhibitors against 3C-like proteases of feline coronaviruses and feline caliciviruses","volume":"89","author":"Kim","year":"2015","journal-title":"J. Virol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"111179","DOI":"10.1016\/j.jinorgbio.2020.111179","article-title":"Structural stability of the SARS-CoV-2 main protease: can metal ions affect function?","volume":"211","author":"Kozak","year":"2020","journal-title":"J. Inorg. Biochem."},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1080\/07391102.2020.1772112","article-title":"Identification of phytochemical inhibitors against main protease of COVID-19 using molecular modeling approaches","author":"Kumar","year":"","journal-title":"J. Biomol. Struct. Dyn."},{"key":"B70","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/07391102.2020.1808072","article-title":"Antitussive noscapine and antiviral drug conjugates as arsenal against COVID-19: a comprehensive chemoinformatics analysis","author":"Kumar","year":"","journal-title":"J. Biomol. Struct. Dyn."},{"key":"B71","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1016\/j.jiph.2020.06.016","article-title":"In silico prediction of potential inhibitors for the Main protease of SARS-CoV-2 using molecular docking and dynamics simulation based drug-repurposing","volume":"13","author":"Kumar","year":"","journal-title":"J. Infect Public Health"},{"key":"B72","doi-asserted-by":"publisher","first-page":"1078","DOI":"10.1126\/science.257.5073.1078","article-title":"Structure-based strategies for drug design and discovery","volume":"257","author":"Kuntz","year":"1992","journal-title":"Science"},{"key":"B73","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1016\/j.febslet.2008.12.059","article-title":"Individual and common inhibitors of coronavirus and picornavirus main proteases","volume":"583","author":"Kuo","year":"2009","journal-title":"FEBS Lett."},{"key":"B74","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1016\/0042-6822(91)90071-i","article-title":"The complete sequence (22 kilobases) of murine coronavirus gene 1 encoding the putative proteases and RNA polymerase","volume":"180","author":"Lee","year":"1991","journal-title":"Virology"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1101\/2020.01.28.922922","article-title":"Therapeutic drugs targeting 2019-nCoV main protease by high-throughput screening","author":"Li","year":"","journal-title":"BioRxiv"},{"key":"B76","doi-asserted-by":"publisher","first-page":"27381","DOI":"10.1073\/pnas.2010470117","article-title":"Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs","volume":"117","author":"Li","year":"","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B77","doi-asserted-by":"publisher","first-page":"e101941","DOI":"10.1371\/journal.pone.0101941","article-title":"Dynamically-driven enhancement of the catalytic machinery of the SARS 3C-like protease by the S284-T285-I286\/A mutations on the extra domain","volume":"9","author":"Lim","year":"2014","journal-title":"PLoS One"},{"key":"B78","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.jgg.2020.02.001","article-title":"Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines","volume":"47","author":"Liu","year":"2020","journal-title":"J. Genet. Genomics"},{"key":"B79","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1016\/S0140-6736(20)30251-8","article-title":"Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding","volume":"395","author":"Lu","year":"2020","journal-title":"The lancet"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.21203\/rs.3.rs-80869\/v1","article-title":"Crystal-structures-guided design of fragment-based drugs for inhibiting the main protease of SARS-CoV-2","author":"Luan","year":"2020","journal-title":"Research square"},{"key":"B81","doi-asserted-by":"publisher","first-page":"95","DOI":"10.2147\/HIV.S79956","article-title":"HIV protease inhibitors: a review of molecular selectivity and toxicity","volume":"7","author":"Lv","year":"2015","journal-title":"HIV AIDS (Auckl)"},{"key":"B82","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1055\/s-0028-1111106","article-title":"Development of ebselen, a glutathione peroxidase mimic, for the prevention and treatment of noise-induced hearing loss","volume":"30","author":"Lynch","year":"2009","journal-title":"Seminars in Hearing"},{"key":"B83","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1038\/s41422-020-0356-z","article-title":"Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease","volume":"30","author":"Ma","year":"2020","journal-title":"Cell Res."},{"key":"B84","doi-asserted-by":"publisher","first-page":"137489","DOI":"10.1016\/j.cplett.2020.137489","article-title":"Identification of potential binders of the main protease 3CLpro of the COVID-19 via structure-based ligand design and molecular modeling","volume":"750","author":"Macchiagodena","year":"2020","journal-title":"Chem. Phys. Lett"},{"key":"B85","doi-asserted-by":"publisher","first-page":"4261","DOI":"10.13040\/IJPSR.0975-8232.11(9).4261-70","article-title":"Molecular docking study reveals the potential repurposing OF histone deacetylase inhibitors against COVID-19","volume":"11","author":"Mamdouh","year":"2020","journal-title":"IJPSR"},{"key":"B86","doi-asserted-by":"publisher","first-page":"2655","DOI":"10.1007\/s00213-016-4319-5","article-title":"Effects of the potential lithium-mimetic, ebselen, on impulsivity and emotional processing","volume":"233","author":"Masaki","year":"2016","journal-title":"Psychopharmacology (Berl)"},{"key":"B87","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1007\/s13337-020-00598-8","article-title":"Structure-based drug designing for potential antiviral activity of selected natural products from Ayurveda against SARS-CoV-2 spike glycoprotein and its cellular receptor","volume":"31","author":"Maurya","year":"2020","journal-title":"VirusDisease"},{"key":"B88","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/s41392-020-0178-y","article-title":"Designing of improved drugs for COVID-19: crystal structure of SARS-CoV-2 main protease Mpro","volume":"5","author":"Mengist","year":"2020","journal-title":"Signal Transduct Target Ther."},{"key":"B89","first-page":"77","article-title":"Postoperative adjuvant use of carmofur for early breast cancer","volume":"49","author":"Morimoto","year":"2003","journal-title":"Osaka City Med. J."},{"key":"B90","doi-asserted-by":"publisher","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":"B91","doi-asserted-by":"publisher","first-page":"165878","DOI":"10.1016\/j.bbadis.2020.165878","article-title":"Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: structural genomics approach","volume":"1866","author":"Naqvi","year":"2020","journal-title":"Biochim. Biophys. Acta (BBA)-Molecular Basis Dis."},{"key":"B92","doi-asserted-by":"publisher","first-page":"12036","DOI":"10.1039\/D0SC04641H","article-title":"Unveiling the molecular mechanism of SARS-CoV-2 main protease inhibition from 137 crystal structures using algebraic topology and deep learning","volume":"11","author":"Nguyen","year":"2020","journal-title":"Chem. Sci."},{"key":"B93","first-page":"295","article-title":"[Study on effectiveness of carmofur (Mifurol) in urogenital carcinoma, especially bladder cancer, as a post-operative adjuvant chemotherapeutic agent]","volume":"33","author":"Nishio","year":"1987","journal-title":"Hinyokika Kiyo"},{"key":"B94","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1016\/j.jtbi.2008.07.030","article-title":"Molecular dynamic simulations analysis of ritonavir and lopinavir as SARS-CoV 3CL(pro) inhibitors","volume":"254","author":"Nukoolkarn","year":"2008","journal-title":"J. Theor. Biol."},{"key":"B95","doi-asserted-by":"publisher","first-page":"954","DOI":"10.3390\/biom10060954","article-title":"Class AG protein-coupled receptor antagonist famotidine as a therapeutic alternative against SARS-CoV2: an in silico analysis","volume":"10","author":"Ortega","year":"2020","journal-title":"Biomolecules"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.26434\/chemrxiv.12209744.v1","article-title":"The structural landscape of SARS-CoV-2 main protease: hints for inhibitor search","author":"Palese","year":"2020","journal-title":"ChemRxiv"},{"key":"B97","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s10096-020-03961-1","article-title":"Transmission of SARS-CoV-2: an update of current literature","volume":"39","author":"Patel","year":"2020","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"B98","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/S0065-3527(06)66005-3","article-title":"The molecular biology of coronavirus","volume":"66","author":"Paul","year":"2006","journal-title":"Adv. Virus Res."},{"key":"B99","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1177\/1098612X17729626","article-title":"Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis","volume":"20","author":"Pedersen","year":"2018","journal-title":"J. Feline Med. Surg."},{"key":"B100","doi-asserted-by":"publisher","first-page":"6595","DOI":"10.1021\/acs.jmedchem.5b01461","article-title":"An overview of severe acute respiratory syndrome-coronavirus (SARS-CoV) 3CL protease inhibitors: peptidomimetics and small molecule Chemotherapy","volume":"59","author":"Pillaiyar","year":"2016","journal-title":"J. Med. Chem."},{"key":"B101","doi-asserted-by":"publisher","first-page":"12544","DOI":"10.1021\/acscatal.0c03420","article-title":"Unraveling the SARS-CoV-2 main protease mechanism using multiscale methods","volume":"10","author":"Ramos-Guzm\u00e1n","year":"2020","journal-title":"ACS Catal."},{"key":"B102","doi-asserted-by":"publisher","first-page":"eabc5332","DOI":"10.1126\/scitranslmed.abc5332","article-title":"3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV-infected mice","volume":"12","author":"Rathnayake","year":"2020","journal-title":"Sci. Transl Med."},{"key":"B103","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/07391102.2020.1797536","article-title":"Identification of a potential SARS-CoV2 inhibitor via molecular dynamics simulations and amino acid decomposition analysis","author":"Razzaghi-Asl","year":"2020","journal-title":"J. Biomol. Struct. Dyn."},{"key":"B104","volume-title":"2-Phenyl-1, 2-benzisoselenazol-3 (2H)-one containing pharmaceutical preparations and process for the treatment of rheumatic diseases: Google Patents","author":"Renson","year":"1982"},{"key":"B105","doi-asserted-by":"crossref","DOI":"10.1145\/3388440.3414919","article-title":"Novel generated peptides for COVID-19 targets","author":"Rossetto","year":"2020"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1101\/2020.03.07.981928","article-title":"Substrate specificity profiling of SARS-CoV-2 Mpro protease provides basis for anti-COVID-19 drug design","author":"Rut","year":"","journal-title":"Biorxiv"},{"key":"B107","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1038\/s41589-020-00689-z","article-title":"SARS-CoV-2 Mpro inhibitors and activity-based probes for patient-sample imaging","volume":"17","author":"Rut","year":"2021","journal-title":"Nat. Chem. Biol."},{"key":"B108","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1016\/j.arcmed.2020.05.001","article-title":"Probable molecular mechanism of remdesivir for the treatment of COVID-19: need to Know more","volume":"51","author":"Saha","year":"2020","journal-title":"Archives Med. Res."},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.26434\/chemrxiv.13246739.v1","article-title":"Molecular docking of Olea europaea and Curcuma Longa compounds as potential drug agents for targeting main-protease of SARS-nCoV2","author":"Saif","year":"2020","journal-title":"ChemRxiv"},{"key":"B110","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1093\/jjco\/hyi147","article-title":"An individual patient data meta-analysis of adjuvant therapy with carmofur in patients with Curatively resected Colon cancer","volume":"35","author":"Sakamoto","year":"2005","journal-title":"Jpn. J. Clin. Oncol."},{"key":"B111","doi-asserted-by":"publisher","first-page":"595273","DOI":"10.3389\/fchem.2020.595273","article-title":"Microsecond MD simulation and multiple-Confirmation virtual screening to identify potential anti-COVID-19 inhibitors against SARS-CoV-2 main protease","volume":"8","author":"Selvaraj","year":"2020","journal-title":"Front. Chem."},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1038\/d41591-020-00019-9","article-title":"15 drugs being tested to treat COVID-19 and how they would work","author":"Shaffer","year":"2020","journal-title":"Nat. Med. News Feature."},{"key":"B113","doi-asserted-by":"publisher","first-page":"21724","DOI":"10.1002\/ddr.21724","article-title":"Probing 3CL protease: rationally designed chemical moieties for COVID-19","volume":"81","author":"Sharma","year":"2020","journal-title":"Drug devel. Res."},{"key":"B114","doi-asserted-by":"publisher","first-page":"24765","DOI":"10.1074\/jbc.M311744200","article-title":"Dissection study on the severe acute respiratory syndrome 3C-like protease reveals the critical role of the extra domain in dimerization of the enzyme: defining the extra domain as a new target for design of highly specific protease inhibitors","volume":"279","author":"Shi","year":"2004","journal-title":"J. Biol. Chem."},{"key":"B115","doi-asserted-by":"publisher","first-page":"5240","DOI":"10.1016\/j.bmc.2005.05.065","article-title":"Inhibition of the severe acute respiratory syndrome 3CL protease by peptidomimetic alpha,beta-unsaturated esters","volume":"13","author":"Shie","year":"2005","journal-title":"Bioorg. Med. Chem."},{"key":"B116","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/07391102.2020.1810778","article-title":"Targeting COVID-19 (SARS-CoV-2) main protease through active phytochemicals of ayurvedic medicinal plants\u2013Withania somnifera (Ashwagandha), Tinospora cordifolia (Giloy) and Ocimum sanctum (Tulsi)\u2013a molecular docking study","author":"Shree","year":"2020","journal-title":"J. Biomol. Struct. Dyn."},{"key":"B117","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1007\/s12250-020-00242-1","article-title":"SARS-Coronavirus-2 Nsp13 possesses NTPase and RNA helicase activities that can Be inhibited by bismuth salts","volume":"35","author":"Shu","year":"2020","journal-title":"Virol. Sin."},{"key":"B118","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.freeradbiomed.2020.06.032","article-title":"Potential therapeutic use of ebselen for COVID-19 and other respiratory viral infections","volume":"156","author":"Sies","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"B120","doi-asserted-by":"publisher","first-page":"1332","DOI":"10.1038\/ncomms2320","article-title":"A safe lithium mimetic for bipolar disorder","volume":"4","author":"Singh","year":"2013","journal-title":"Nat. Commun."},{"key":"B121","doi-asserted-by":"publisher","DOI":"10.26434\/chemrxiv.12581819.v1","article-title":"Computational studies towards identification of lead herbal compounds of medicinal importance for development of nutraceutical against COVID-19","author":"Srivastav","year":"2020","journal-title":"ChemRxiv"},{"key":"B122","doi-asserted-by":"publisher","first-page":"942","DOI":"10.3390\/v12090942","article-title":"Optimization rules for SARS-CoV-2 Mpro antivirals: ensemble docking and exploration of the coronavirus protease active site","volume":"12","author":"Stoddard","year":"2020","journal-title":"Viruses"},{"key":"B123","doi-asserted-by":"publisher","DOI":"10.26434\/chemrxiv.11637294.v3","article-title":"Homology models of coronavirus 2019-nCoV 3CLpro protease","author":"Stoermer","year":"2020","journal-title":"Chemrxiv"},{"key":"B124","doi-asserted-by":"publisher","DOI":"10.1101\/2020.04.13.038687","article-title":"Discovery of baicalin and baicalein as novel, natural product inhibitors of SARS-CoV-2 3CL protease in vitro","author":"Su","year":"2020","journal-title":"bioRxiv"},{"key":"B125","doi-asserted-by":"publisher","first-page":"10626","DOI":"10.26434\/chemrxiv.12283967","article-title":"Revealing the molecular mechanisms of proteolysis of SARS-CoV-2 Mpro from QM\/MM computational methods","volume":"11","author":"Swiderek","year":"2020","journal-title":"Chem. Sci."},{"key":"B126","doi-asserted-by":"publisher","DOI":"10.1101\/2020.03.03.972133","article-title":"AI-aided design of novel targeted covalent inhibitors against SARS-CoV-2","author":"Tang","year":"2020","journal-title":"bioRxiv"},{"key":"B127","doi-asserted-by":"publisher","first-page":"2305","DOI":"10.1099\/vir.0.19424-0","article-title":"Mechanisms and enzymes involved in SARS coronavirus genome expression","volume":"84","author":"Thiel","year":"2003","journal-title":"J. Gen. Virol."},{"key":"B128","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1038\/nrd2092","article-title":"Targeting proteases: successes, failures and future prospects","volume":"5","author":"Turk","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"B129","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/j.jpha.2020.03.009","article-title":"Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants","volume":"10","author":"ul Qamar","year":"2020","journal-title":"J. Pharm. Anal."},{"key":"B130","doi-asserted-by":"publisher","first-page":"127377","DOI":"10.1016\/j.bmcl.2020.127377","article-title":"The SARS-CoV-2 main protease as drug target","volume":"30","author":"Ullrich","year":"2020","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"B131","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1016\/S0969-2126(00)00060-5","article-title":"Structure-based drug design: progress, results and challenges","volume":"2","author":"Verlinde","year":"1994","journal-title":"Structure"},{"key":"B132","doi-asserted-by":"publisher","first-page":"4282","DOI":"10.1038\/s41467-020-18096-2","article-title":"Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication","volume":"11","author":"Vuong","year":"2020","journal-title":"Nat. Commun."},{"key":"B133","doi-asserted-by":"crossref","DOI":"10.1145\/3388440.3414706","article-title":"Impactful mutations in Mpro of the SARS-CoV-2 proteome","author":"Wolfe","year":"2020"},{"key":"B134","doi-asserted-by":"publisher","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 Pharmaceutica Sinica B"},{"key":"B135","doi-asserted-by":"publisher","DOI":"10.1101\/2020.01.27.921627","article-title":"Nelfinavir was predicted to be a potential inhibitor of 2019-nCov main protease by an integrative approach combining homology modelling, molecular docking and binding free energy calculation","author":"Xu","year":"2020","journal-title":"bioRxiv"},{"key":"B136","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1016\/j.jmb.2006.11.073","article-title":"Production of authentic SARS-CoV M(pro) with enhanced activity: application as a novel tag-cleavage endopeptidase for protein overproduction","volume":"366","author":"Xue","year":"2007","journal-title":"J. Mol. Biol."},{"key":"B137","doi-asserted-by":"publisher","first-page":"2515","DOI":"10.1128\/JVI.02114-07","article-title":"Structures of two coronavirus main proteases: implications for substrate binding and antiviral drug design","volume":"82","author":"Xue","year":"2008","journal-title":"J. Virol."},{"key":"B138","doi-asserted-by":"publisher","first-page":"e324","DOI":"10.1371\/journal.pbio.0030324","article-title":"Design of wide-spectrum inhibitors targeting coronavirus main proteases","volume":"3","author":"Yang","year":"2005","journal-title":"PLoS Biol."},{"key":"B139","doi-asserted-by":"publisher","first-page":"13190","DOI":"10.1073\/pnas.1835675100","article-title":"The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor","volume":"100","author":"Yang","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"B140","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1126\/science.abb3405","article-title":"Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved \u03b1-ketoamide inhibitors","volume":"368","author":"Zhang","year":"","journal-title":"Science"},{"key":"B141","doi-asserted-by":"publisher","first-page":"4562","DOI":"10.1021\/acs.jmedchem.9b01828","article-title":"\u03b1-Ketoamides as broad-spectrum inhibitors of coronavirus and enterovirus replication: structure-based design, synthesis, and activity assessment","volume":"63","author":"Zhang","year":"","journal-title":"J. Med. Chem."},{"key":"B142","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1080\/22221751.2020.1729071","article-title":"Molecular and serological investigation of 2019-nCoV infected patients: implication of multiple shedding routes","volume":"9","author":"Zhang","year":"","journal-title":"Emerging microbes & infections"},{"key":"B143","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.crmicr.2020.06.003","article-title":"Minireview of progress in the structural study of SARS-CoV-2 proteins","volume":"1","author":"Zhu","year":"2020","journal-title":"Curr. Res. Microb. Sci."},{"key":"B144","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1099\/0022-1317-81-4-853","article-title":"Virus-encoded proteinases and proteolytic processing in the Nidovirales","volume":"81","author":"Ziebuhr","year":"2000","journal-title":"J. Gen. Virol."},{"key":"B145","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/nrd.2015.37","article-title":"Coronaviruses - drug discovery and therapeutic options","volume":"15","author":"Zumla","year":"2016","journal-title":"Nat. Rev. Drug Discov."}],"container-title":["Frontiers in Chemistry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2021.622898\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T02:05:19Z","timestamp":1671588319000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2021.622898\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,12]]},"references-count":144,"alternative-id":["10.3389\/fchem.2021.622898"],"URL":"https:\/\/doi.org\/10.3389\/fchem.2021.622898","relation":{},"ISSN":["2296-2646"],"issn-type":[{"value":"2296-2646","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,12]]},"article-number":"622898"}}