{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T02:07:50Z","timestamp":1784686070057,"version":"3.55.0"},"reference-count":67,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,1,30]],"date-time":"2021-01-30T00:00:00Z","timestamp":1611964800000},"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 synthesis of \u03b1-fluorinated methyl ketones has always been challenging. New methods based on the homologation chemistry via nucleophilic halocarbenoid transfer, carried out recently in our labs, allowed us to design and synthesize a target-directed dipeptidyl \u03b1,\u03b1-difluoromethyl ketone (DFMK) 8 as a potential antiviral agent with activity against human coronaviruses. The ability of the newly synthesized compound to inhibit viral replication was evaluated by a viral cytopathic effect (CPE)-based assay performed on MCR5 cells infected with one of the four human coronaviruses associated with respiratory distress, i.e., hCoV-229E, showing antiproliferative activity in the micromolar range (EC50 = 12.9 \u00b1 1.22 \u00b5M), with a very low cytotoxicity profile (CC50 = 170 \u00b1 3.79 \u00b5M, 307 \u00b1 11.63 \u00b5M, and 174 \u00b1 7.6 \u00b5M for A549, human embryonic lung fibroblasts (HELFs), and MRC5 cells, respectively). Docking and molecular dynamics simulations studies indicated that 8 efficaciously binds to the intended target hCoV-229E main protease (Mpro). Moreover, due to the high similarity between hCoV-229E Mpro and SARS-CoV-2 Mpro, we also performed the in silico analysis towards the second target, which showed results comparable to those obtained for hCoV-229E Mpro and promising in terms of energy of binding and docking pose.<\/jats:p>","DOI":"10.3390\/ijms22031398","type":"journal-article","created":{"date-parts":[[2021,1,30]],"date-time":"2021-01-30T08:56:01Z","timestamp":1611996961000},"page":"1398","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Pseudo-Dipeptide Bearing \u03b1,\u03b1-Difluoromethyl Ketone Moiety as Electrophilic Warhead with Activity against Coronaviruses"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5881-7142","authenticated-orcid":false,"given":"Andrea","family":"Citarella","sequence":"first","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, V.le F. Stagno d\u2019Alcontres 31, 98166 Messina, Italy"},{"name":"Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Gentile","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Catania, V.le A. Doria, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5039-2151","authenticated-orcid":false,"given":"Antonio","family":"Rescifina","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Catania, V.le A. Doria, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6004-5196","authenticated-orcid":false,"given":"Anna","family":"Piperno","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, V.le F. Stagno d\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2888-8999","authenticated-orcid":false,"given":"Barbara","family":"Mognetti","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Systems Biology, University of Torino, Via Accademia Albertina 13, 10123 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1583-9146","authenticated-orcid":false,"given":"Giorgio","family":"Gribaudo","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Systems Biology, University of Torino, Via Accademia Albertina 13, 10123 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8519-7724","authenticated-orcid":false,"given":"Maria Teresa","family":"Sciortino","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, V.le F. Stagno d\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Holzer","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3037-5930","authenticated-orcid":false,"given":"Vittorio","family":"Pace","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria"},{"name":"Department of Chemistry, University of Torino, Via P. Giuria 7, 10125 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9294-6033","authenticated-orcid":false,"given":"Nicola","family":"Micale","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, V.le F. Stagno d\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1093\/ije\/dyaa033","article-title":"The SARS, MERS and novel coronavirus (COVID-19) epidemics, the newest and biggest global health threats: What lessons have we learned?","volume":"49","author":"Peeri","year":"2020","journal-title":"Int. J. Epidemiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1097\/COH.0000000000000588","article-title":"HIV treatment and prevention 2019: Current standards of care","volume":"15","author":"Phanuphak","year":"2020","journal-title":"Curr. Opin. HIV AIDS"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1159\/000500963","article-title":"Treatment of chronic hepatitis C: Efficacy, side effects and complications","volume":"35","author":"Sandmann","year":"2019","journal-title":"Visc. Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Duncan, J.D., Urbanowicz, R.A., Tarr, A.W., and Ball, J.K. (2020). Hepatitis C virus vaccine: Challenges and prospects. Vaccines, 8.","DOI":"10.3390\/vaccines8010090"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Crimi, S., Fiorillo, L., Bianchi, A., D\u2019Amico, C., Amoroso, G., Gorassini, F., Mastroieni, R., Marino, S., Scoglio, C., and Catalano, F. (2019). Herpes virus, oral clinical signs and QoL: Systematic review of recent data. Viruses, 11.","DOI":"10.3390\/v11050463"},{"key":"ref_6","unstructured":"Agency, E.M. (2020). Summary on Compassionate Use Remdesivir Gilead, European Medicines Agency."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1208\/s12248-020-00459-8","article-title":"Remdesivir for treatment of COVID-19: Combination of pulmonary and IV administration may offer additional benefit","volume":"22","author":"Sun","year":"2020","journal-title":"AAPS J."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Jin, Y., Yang, H., Ji, W., Wu, W., Chen, S., Zhang, W., and Duan, G. (2020). Virology, epidemiology, pathogenesis, and control of COVID-19. Viruses, 12.","DOI":"10.3390\/v12040372"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1111\/cbdd.13326","article-title":"Discovery of benzimidazole-based Leishmania mexicana cysteine protease CPB 2.8 \u0394 CTE inhibitors as potential therapeutics for leishmaniasis","volume":"92","author":"Ferro","year":"2018","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/s10534-017-0007-0","article-title":"Gold compounds as cysteine protease inhibitors: Perspectives for pharmaceutical application as antiparasitic agents","volume":"30","author":"Massai","year":"2017","journal-title":"BioMetals"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"30628","DOI":"10.1039\/C6RA05557E","article-title":"Targeting of the leishmania Mexicana cysteine protease CPB2. 8\u0394CTE by decorated fused benzo [b] thiophene scaffold","volume":"6","author":"Scala","year":"2016","journal-title":"RSC Adv."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1111\/cbdd.13124","article-title":"Ensemble-based ADME\u2013Tox profiling and virtual screening for the discovery of new inhibitors of the Leishmania mexicana cysteine protease CPB2. 8\u0394CTE","volume":"91","author":"Scala","year":"2018","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Citarella, A., and Micale, N. (2020). Peptidyl fluoromethyl ketones and their applications in medicinal chemistry. Molecules, 25.","DOI":"10.3390\/molecules25174031"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1039\/B711844A","article-title":"Understanding organofluorine chemistry. An introduction to the C\u2013F bond","volume":"37","year":"2008","journal-title":"Chem. Soc. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"11116","DOI":"10.1039\/C6CC05775F","article-title":"Rh-Catalyzed arylation of fluorinated ketones with arylboronic acids","volume":"52","author":"Dobson","year":"2016","journal-title":"Chem. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/S0022-1139(00)82241-1","article-title":"A semi-empirical and ab-initio analysis of fluoroketones as reactive electrophiles","volume":"53","author":"Linderman","year":"1991","journal-title":"J. Fluor. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2915","DOI":"10.3762\/bjoc.13.284","article-title":"Conformational preferences of \u03b1-fluoroketones may influence their reactivity","volume":"13","author":"Pattison","year":"2017","journal-title":"Beilstein J. Org. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3520","DOI":"10.1002\/ejoc.201800532","article-title":"Methods for the Synthesis of \u03b1, \u03b1-Difluoroketones","volume":"2018","author":"Pattison","year":"2018","journal-title":"Eur. J. Org. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"12487","DOI":"10.1039\/C9CC05771D","article-title":"CF2H as a hydrogen bond donor group for the fine tuning of peptide bond geometry with difluoromethylated pseudoprolines","volume":"55","author":"Malquin","year":"2019","journal-title":"Chem. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1021\/ar00156a004","article-title":"Equilibrium acidities in dimethyl sulfoxide solution","volume":"21","author":"Bordwell","year":"1988","journal-title":"Acc. Chem. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1021\/jo00111a021","article-title":"Hydrogen bond donor properties of the difluoromethyl group","volume":"60","author":"Erickson","year":"1995","journal-title":"J. Org. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9325","DOI":"10.1021\/jacs.7b04457","article-title":"CF2H, a hydrogen bond donor","volume":"139","author":"Sessler","year":"2017","journal-title":"J. Am. Chem. Soc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4405","DOI":"10.1016\/j.bmcl.2015.09.019","article-title":"Difluoromethyl ketones: Potent inhibitors of wild type and carbamate-insensitive G119S mutant Anopheles gambiae acetylcholinesterase","volume":"25","author":"Camerino","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2697","DOI":"10.1016\/j.bmcl.2018.04.003","article-title":"Agonists of the \u03b3-aminobutyric acid type B (GABAB) receptor derived from \u03b2-hydroxy and \u03b2-amino difluoromethyl ketones","volume":"28","author":"Sowaileh","year":"2018","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/0003-9861(90)90528-7","article-title":"Structure-activity studies of fluoroketone inhibitors of \u03b1-lytic protease and human leukocyte elastase","volume":"280","author":"Govardhan","year":"1990","journal-title":"Arch. Biochem. Biophysc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3760","DOI":"10.1021\/bi00361a005","article-title":"Inhibition of serine proteases by peptidyl fluoromethyl ketones","volume":"25","author":"Imperiali","year":"1986","journal-title":"Biochemistry"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Sham, H.L., Wideburg, N.E., Spanton, S.G., Kohlbrenner, W.E., Betebenner, D.A., Kempf, D.J., Norbeck, D.W., Plattner, J.J., and Erickson, J.W. (1991). Synthesis of (2S, 5S, 4R)-2, 5-diamino-3, 3-difluoro-1, 6-diphenylhydroxyhexane: The core unit of a potent HIV proteinase inhibitor. J. Chem. Soc. Chem. Commun., 110\u2013112.","DOI":"10.1039\/c39910000110"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"11133","DOI":"10.1039\/c3cc46266h","article-title":"Trifluoromethyl ketones: Properties, preparation, and application","volume":"49","author":"Kelly","year":"2013","journal-title":"Chem. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4652","DOI":"10.1016\/j.bmc.2008.02.040","article-title":"Design, synthesis, and evaluation of trifluoromethyl ketones as inhibitors of SARS-CoV 3CL protease","volume":"16","author":"Shao","year":"2008","journal-title":"Bioorg. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1021\/acsmedchemlett.8b00511","article-title":"Synthesis and anti-HIV profile of a novel tetrahydroindazolylbenzamide derivative obtained by oxazolone chemistry","volume":"10","author":"Scala","year":"2018","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Gentile, D., Patamia, V., Scala, A., Sciortino, M.T., Piperno, A., and Rescifina, A. (2020). Putative inhibitors of SARS-CoV-2 main protease from a library of marine natural products: A virtual screening and molecular modeling study. Mar. Drugs, 18.","DOI":"10.20944\/preprints202003.0372.v1"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.2174\/0929867321666131228205935","article-title":"Recent highlights in the synthesis of anti-HCV ribonucleosides","volume":"21","author":"Piperno","year":"2014","journal-title":"Curr. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1002\/adsc.201500840","article-title":"Catalysis, chemoselective addition of halomethyllithiums to functionalized isatins: A straightforward access to spiro-epoxyoxindoles","volume":"358","author":"Pace","year":"2016","journal-title":"Adv. Synth. Catal."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1002\/adsc.201301042","article-title":"Chemoselective additions of chloromethyllithium carbenoid to cyclic enones: A direct access to chloromethyl allylic alcohols","volume":"356","author":"Pace","year":"2014","journal-title":"Adv. Synth. Catal."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2897","DOI":"10.1055\/s-0034-1379209","article-title":"Homologation of isocyanates with lithium carbenoids: A straightforward access to \u03b1-halomethyl-and \u03b1, \u03b1-dihalomethylamides","volume":"46","author":"Pace","year":"2014","journal-title":"Synthesis"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"12677","DOI":"10.1002\/anie.201706236","article-title":"Efficient access to all-carbon quaternary and tertiary alpha-functionalized homoallyl-type aldehydes from ketones","volume":"56","author":"Pace","year":"2017","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1055\/s-0036-1588139","article-title":"New perspectives in lithium carbenoid mediated homologations","volume":"28","author":"Pace","year":"2017","journal-title":"Synlett"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1002\/adsc.201201043","article-title":"Chemoselective synthesis of N-substituted \u03b1-amino-\u03b1\u2032-chloro ketones via chloromethylation of glycine-derived weinreb amides","volume":"355","author":"Pace","year":"2013","journal-title":"Adv. Synth. Catal."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7584","DOI":"10.1039\/C6CC03532A","article-title":"Highly efficient synthesis of functionalized alpha-oxyketones via Weinreb amides homologation with alpha-oxygenated organolithiums","volume":"52","author":"Pace","year":"2016","journal-title":"Chem. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7764","DOI":"10.1021\/jo401236t","article-title":"Synthesis of \u03b1, \u03b2-unsaturated \u03b1\u2019-haloketones through the chemoselective addition of halomethyllithiums to weinreb amides","volume":"78","author":"Pace","year":"2013","journal-title":"J. Org. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"8383","DOI":"10.1039\/c3cc44255a","article-title":"Addition of lithium carbenoids to isocyanates: A direct access to synthetically useful N-substituted 2-haloacetamides","volume":"49","author":"Pace","year":"2013","journal-title":"Chem. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"12960","DOI":"10.1039\/C9CC06929A","article-title":"Highly chemoselective difluoromethylative homologation of iso(thio)cyanates: Expeditious access to unprecedented alpha, alpha-difluoro(thio)amides","volume":"55","author":"Miele","year":"2019","journal-title":"Chem. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8261","DOI":"10.1021\/acs.orglett.9b03024","article-title":"Direct and chemoselective synthesis of tertiary difluoroketones via weinreb amide homologation with a CHF2-carbene equivalent","volume":"21","author":"Miele","year":"2019","journal-title":"ACS Org. Lett."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2479","DOI":"10.1002\/anie.201812525","article-title":"Telescoped, divergent, chemoselective C1 and C1-C1 homologation of imine surrogates: Access to quaternary chloro- and halomethyl-trifluoromethyl aziridines","volume":"58","author":"Ielo","year":"2019","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6692","DOI":"10.1039\/C8CC02499E","article-title":"Homologation chemistry with nucleophilic alpha-substituted organometallic reagents: Chemocontrol, new concepts and (solved) challenges","volume":"54","author":"Castoldi","year":"2018","journal-title":"Chem. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"13648","DOI":"10.1021\/jacs.7b07891","article-title":"Exploiting a \u201cBeast\u201d in carbenoid chemistry: Development of a straightforward direct nucleophilic fluoromethylation strategy","volume":"139","author":"Parisi","year":"2017","journal-title":"J. Am. Chem. Soc."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.1016\/j.tet.2018.03.034","article-title":"Merging lithium carbenoid homologation and enzymatic reduction: A combinative approach to the HIV-protease inhibitor nelfinavir","volume":"74","author":"Castoldi","year":"2018","journal-title":"Tetrahedron"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1002\/jccs.199400013","article-title":"Synthesis of aryl \u03b1, \u03b1-difluoroalkyl ketones as potent inhibitors of cholesterol esterase","volume":"41","author":"Lin","year":"1994","journal-title":"J. Chin. Chem. Soc."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1016\/S0960-894X(00)00287-0","article-title":"Difluoroketones as inhibitors of matrix metalloprotease-13","volume":"10","author":"Reiter","year":"2000","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1139\/v60-056","article-title":"The acidity of some aromatic fluoro alcohols and ketones","volume":"38","author":"Stewart","year":"1960","journal-title":"Can. J. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/bs.aivir.2018.01.001","article-title":"Hosts and sources of endemic human coronaviruses","volume":"Volume 100","author":"Corman","year":"2018","journal-title":"Advances in Virus Research"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"104541","DOI":"10.1016\/j.antiviral.2019.104541","article-title":"Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase","volume":"169","author":"Brown","year":"2019","journal-title":"Antivir. Res."},{"key":"ref_53","doi-asserted-by":"crossref","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":"ref_54","doi-asserted-by":"crossref","first-page":"3992","DOI":"10.1128\/jvi.71.5.3992-3997.1997","article-title":"Biosynthesis, purification, and characterization of the human coronavirus 229E 3C-like proteinase","volume":"71","author":"Ziebuhr","year":"1997","journal-title":"J. Virol."},{"key":"ref_55","doi-asserted-by":"crossref","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":"2020","journal-title":"J. Med. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"22677","DOI":"10.1038\/srep22677","article-title":"Structure of main protease from human coronavirus NL63: Insights for wide spectrum anti-coronavirus drug design","volume":"6","author":"Wang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/s41586-020-2223-y","article-title":"Structure of M(pro) from SARS-CoV-2 and discovery of its inhibitors","volume":"582","author":"Jin","year":"2020","journal-title":"Nature"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1111\/j.1365-2672.2008.03927.x","article-title":"New cell-based indicator assays for the detection of human cytomegalovirus infection and screening of inhibitors of viral immediate-early 2 protein activity","volume":"105","author":"Luganini","year":"2008","journal-title":"J. Appl. Microbiol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Gentile, D., Fuochi, V., Rescifina, A., and Furneri, P.M. (2020). New anti SARS-Cov-2 targets for quinoline derivatives chloroquine and hydroxychloroquine. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21165856"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1021\/acsmedchemlett.9b00661","article-title":"Sigma receptor ligands carrying a nitric oxide donor nitrate moiety: Synthesis, in silico, and biological evaluation","volume":"11","author":"Amata","year":"2020","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1002\/cmdc.201900594","article-title":"Repurposing of FDA-approved drugs for treating iatrogenic botulism: A paired 3D-QSAR\/docking approach","volume":"15","author":"Floresta","year":"2020","journal-title":"Chem. Med. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Floresta, G., Gentile, D., Perrini, G., Patamia, V., and Rescifina, A. (2019). Computational tools in the discovery of FABP4 ligands: A statistical and molecular modeling approach. Mar. Drugs, 17.","DOI":"10.20944\/preprints201909.0063.v1"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Floresta, G., Amata, E., Gentile, D., Romeo, G., Marrazzo, A., Pittal\u00e0, V., Salerno, L., and Rescifina, A. (2019). Fourfold filtered statistical\/computational approach for the identification of imidazole compounds as HO-1 inhibitors from natural products. Mar. Drugs, 17.","DOI":"10.3390\/md17020113"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Floresta, G., Dichiara, M., Gentile, D., Prezzavento, O., Marrazzo, A., Rescifina, A., and Amata, E. (2019). Morphing of ibogaine: A successful attempt into the search for sigma-2 receptor ligands. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030488"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1002\/prot.10104","article-title":"Increasing the precision of comparative models with YASARA NOVA\u2014A self-parameterizing force field","volume":"47","author":"Krieger","year":"2002","journal-title":"Prot. Struct. Funct. Bioinform."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2981","DOI":"10.1093\/bioinformatics\/btu426","article-title":"YASARA View\u2014Molecular graphics for all devices\u2014From smartphones to workstations","volume":"30","author":"Krieger","year":"2014","journal-title":"Bioinform."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1007\/s00894-007-0233-4","article-title":"Optimization of parameters for semiempirical methods V: Modification of NDDO approximations and application to 70 elements","volume":"13","author":"Stewart","year":"2007","journal-title":"J. Mol. 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