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Proteases are promising targets for the treatment of viral infections. In this study, we collected and profiled 170 protease sequences from 125 viruses that infect humans. Approximately 73 of them are viral 3-chymotrypsin-like proteases (3CLpro), and 11 are pepsin-like aspartic proteases (PAPs). Their sequences, structures, and substrate characteristics were carefully analyzed to identify their conserved nature for proposing a pan-3CLpro or pan-PAPs inhibitor design strategy. To achieve this, we used computational prediction and modeling methods to predict the binding complex structures for those 73 3CLpro with 4 protease inhibitors of SARS-CoV-2 and 11 protease inhibitors of HCV. Similarly, the complex structures for the 11 viral PAPs with 9 protease inhibitors of HIV were also obtained. The binding affinities between these compounds and proteins were also evaluated to assess their pan-protease inhibition via MM-GBSA. Based on the drugs targeting viral 3CLpro and PAPs, repositioning of the active compounds identified several potential uses for these drug molecules. As a result, Compounds 1\u20132, modified based on the structures of Ray1216 and Asunaprevir, indicate potential inhibition of DENV protease according to our computational simulation results. These studies offer ideas and insights for future research in the design of broad-spectrum antiviral drugs.<\/jats:p>","DOI":"10.3390\/molecules29010225","type":"journal-article","created":{"date-parts":[[2023,12,31]],"date-time":"2023-12-31T06:00:21Z","timestamp":1704002421000},"page":"225","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Computer-Aided Prediction of the Interactions of Viral Proteases with Antiviral Drugs: Antiviral Potential of Broad-Spectrum Drugs"],"prefix":"10.3390","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6475-3974","authenticated-orcid":false,"given":"Pengxuan","family":"Ren","sequence":"first","affiliation":[{"name":"School of Life Science and Technology, Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiwei","family":"Li","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4714-6504","authenticated-orcid":false,"given":"Shihang","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianglei","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1468-5568","authenticated-orcid":false,"given":"Fang","family":"Bai","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China"},{"name":"School of Information Science and Technology, ShanghaiTech University, Shanghai 201210, China"},{"name":"Shanghai Clinical Research and Trial Center, Shanghai 201210, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1056\/NEJMoa2001017","article-title":"A novel coronavirus from patients with pneumonia in China, 2019","volume":"382","author":"Zhu","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/S0140-6736(20)30185-9","article-title":"A novel coronavirus outbreak of global health concern","volume":"395","author":"Wang","year":"2020","journal-title":"Lancet"},{"key":"ref_3","unstructured":"(2023, November 01). Statement on the Fifteenth Meeting of the IHR (2005) Emergency Committee on the COVID-19 Pandemic. Available online: https:\/\/www.who.int\/news\/item\/05-05-2023-statement-on-the-fifteenth-meeting-of-the-international-health-regulations-(2005)-emergency-committee-regarding-the-coronavirus-disease-(covid-19)-pandemic."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1126\/science.aap7463","article-title":"The Global Virome Project","volume":"359","author":"Carroll","year":"2018","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1038\/nature22975","article-title":"Host and viral traits predict zoonotic spillover from mammals","volume":"546","author":"Olival","year":"2017","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.patbio.2008.02.015","article-title":"The human HTLV-3 and HTLV-4 retroviruses: New members of the HTLV family","volume":"57","author":"Mahieux","year":"2009","journal-title":"Pathol. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/s41586-021-04111-z","article-title":"Independent infections of porcine deltacoronavirus among Haitian children","volume":"600","author":"Lednicky","year":"2021","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1038\/nm1024","article-title":"Identification of a new human coronavirus","volume":"10","author":"Pyrc","year":"2004","journal-title":"Nat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1093\/cid\/ciab456","article-title":"Novel canine coronavirus isolated from a hospitalized patient with pneumonia in east malaysia","volume":"74","author":"Vlasova","year":"2021","journal-title":"Clin. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"57","DOI":"10.3390\/v1010057","article-title":"More and more coronaviruses: Human coronavirus HKU1","volume":"1","author":"Woo","year":"2009","journal-title":"Viruses"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.ijbiomac.2021.01.076","article-title":"Trends and strategies to combat viral infections: A review on FDA approved antiviral drugs","volume":"172","author":"Tompa","year":"2021","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_12","doi-asserted-by":"crossref","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":"2020","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"10773","DOI":"10.1073\/pnas.90.22.10773","article-title":"Proteolytic processing and membrane association of putative nonstructural proteins of hepatitis C virus","volume":"90","author":"Hijikata","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"22725","DOI":"10.1074\/jbc.R110.125294","article-title":"Hepatitis C virus non-structural protein 3 (HCV NS3): A multifunctional antiviral target","volume":"285","author":"Raney","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1039\/b208248a","article-title":"HIV-1 protease: Mechanism and drug discovery","volume":"1","author":"Brik","year":"2003","journal-title":"Org. Biomol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1126\/science.abl4784","article-title":"An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19","volume":"374","author":"Owen","year":"2021","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1056\/NEJMoa2118542","article-title":"Oral Nirmatrelvir for high-risk, nonhospitalized adults with COVID-19","volume":"386","author":"Hammond","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6463","DOI":"10.1038\/s41467-023-42102-y","article-title":"Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir","volume":"14","author":"Jiang","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Chen, X., Huang, X., Ma, Q., Kuzmi\u010d, P., Zhou, B., Xu, J., Liu, B., Jiang, H., Zhang, W., and Yang, C. (2023). Inhibition mechanism and antiviral activity of an \u03b1-ketoamide based SARS-CoV-2 main protease inhibitor. bioRxiv.","DOI":"10.21203\/rs.3.rs-2634509\/v1"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6499","DOI":"10.1021\/acs.jmedchem.2c00117","article-title":"Discovery of S-217622, a noncovalent oral SARS-CoV-2 3CL protease inhibitor clinical candidate for treating COVID-19","volume":"65","author":"Unoh","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1056\/NEJMoa1009482","article-title":"Boceprevir for previously treated chronic HCV genotype 1 infection","volume":"364","author":"Bacon","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3","DOI":"10.2174\/187152606776056706","article-title":"Discovery and development of VX-950, a novel, covalent, and reversible inhibitor of Hepatitis C virus NS3.4A serine protease","volume":"6","author":"Lin","year":"2006","journal-title":"Infect. Disord.\u2014Drug Targets"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1021\/ml9000276","article-title":"Discovery of narlaprevir (SCH 900518): A potent, second generation HCV NS3 serine protease inhibitor","volume":"1","author":"Arasappan","year":"2010","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1056\/NEJMoa1104430","article-title":"Preliminary study of two antiviral agents for Hepatitis C genotype 1","volume":"366","author":"Lok","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1021\/jm400164c","article-title":"Discovery of Danoprevir (ITMN-191\/R7227), a highly selective and potent inhibitor of Hepatitis C Virus (HCV) NS3\/4A protease","volume":"57","author":"Jiang","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3261","DOI":"10.2174\/0929867321666140706125950","article-title":"ABT-450: A novel protease inhibitor for the treatment of Hepatitis C Virus infection","volume":"21","author":"Gentile","year":"2014","journal-title":"Curr. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1128\/AAC.01058-08","article-title":"In Vitro activity and preclinical profile of TMC435350, a potent Hepatitis C Virus protease inhibitor","volume":"53","author":"Lin","year":"2009","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1021\/jm9015526","article-title":"Discovery of Vaniprevir (MK-7009), a macrocyclic Hepatitis C Virus NS3\/4a protease inhibitor","volume":"53","author":"McCauley","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1021\/ml300017p","article-title":"Discovery of MK-5172, a macrocyclic Hepatitis C Virus NS3\/4a protease inhibitor","volume":"3","author":"Harper","year":"2012","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2428","DOI":"10.1016\/j.bmcl.2019.03.037","article-title":"Discovery of the pan-genotypic hepatitis C virus NS3\/4A protease inhibitor voxilaprevir (GS-9857): A component of Vosevi\u00ae","volume":"29","author":"Taylor","year":"2019","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_31","first-page":"10","article-title":"In Vitro antiviral activity and resistance profile of the next-generation Hepatitis C Virus NS3\/4A protease inhibitor Glecaprevir","volume":"62","author":"Tripathi","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zephyr, J., Nageswara Rao, D., Vo, S.V., Henes, M., Kosovrasti, K., Matthew, A.N., Hedger, A.K., Timm, J., Chan, E.T., and Ali, A. (2022). Deciphering the molecular mechanism of HCV protease inhibitor Fluorination as a general approach to avoid drug resistance. J. Mol. Biol., 434.","DOI":"10.1016\/j.jmb.2022.167503"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1126\/science.6601823","article-title":"Isolation of Human T-Cell Leukemia Virus in Acquired Immune Deficiency Syndrome (AIDS)","volume":"220","author":"Gallo","year":"1983","journal-title":"Science"},{"key":"ref_34","first-page":"1","article-title":"Saquinavir (Invirase): First protease inhibitor approved--reimbursement, information hotline numbers","volume":"237","author":"James","year":"1995","journal-title":"AIDS Treat. News"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1021\/jm970636+","article-title":"Discovery of Ritonavir, a potent inhibitor of HIV protease with high oral bioavailability and clinical efficacy","volume":"41","author":"Kempf","year":"1998","journal-title":"J. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4096","DOI":"10.1073\/pnas.91.9.4096","article-title":"L-735,524: An orally bioavailable human immunodeficiency virus type 1 protease inhibitor","volume":"91","author":"Vacca","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3979","DOI":"10.1021\/jm9704098","article-title":"Viracept (Nelfinavir Mesylate, AG1343):\u2009 a potent, orally bioavailable inhibitor of HIV-1 protease","volume":"40","author":"Kaldor","year":"1997","journal-title":"J. Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/0166-3542(95)00916-7","article-title":"In vitro antiviral activity of 141W94 (VX-478) in combination with other antiretroviral agents","volume":"29","author":"Clair","year":"1996","journal-title":"Antivir. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3218","DOI":"10.1128\/AAC.42.12.3218","article-title":"ABT-378, a highly potent inhibitor of the Human Immunodeficiency Virus protease","volume":"42","author":"Sham","year":"1998","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1128\/AAC.44.8.2093-2099.2000","article-title":"BMS-232632, a highly potent Human Immunodeficiency Virus protease inhibitor that can be used in combination with other available antiretroviral agents","volume":"44","author":"Robinson","year":"2000","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1038\/nrd1907","article-title":"Tipranavir","volume":"4","author":"Flexner","year":"2005","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1517\/14656566.8.12.1951","article-title":"Darunavir (TMC114): A new HIV-1 protease inhibitor","volume":"8","author":"Molina","year":"2007","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1186\/s12985-016-0561-z","article-title":"Biological function of Foot-and-mouth disease virus non-structural proteins and non-coding elements","volume":"13","author":"Gao","year":"2016","journal-title":"Virol. J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1016\/j.apsb.2021.08.017","article-title":"Enterovirus A71 antivirals: Past, present, and future","volume":"12","author":"Wang","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.1128\/AAC.43.10.2444","article-title":"In Vitro antiviral activity of AG7088, a potent inhibitor of Human Rhinovirus 3C protease","volume":"43","author":"Patick","year":"1999","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"9438","DOI":"10.1021\/acs.jmedchem.5b00762","article-title":"Recent advances in the discovery of Norovirus therapeutics","volume":"58","author":"Kim","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5622","DOI":"10.1021\/acs.jmedchem.5b01653","article-title":"The medicinal chemistry of Dengue Virus","volume":"59","author":"Behnam","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Lim, Y.X., Ng, Y.L., Tam, J.P., and Liu, D.X. (2016). Human Coronaviruses: A review of virus\u2013host interactions. Diseases, 4.","DOI":"10.3390\/diseases4030026"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1128\/jvi.61.5.1301-1309.1987","article-title":"Processing of the Semliki Forest virus structural polyprotein: Role of the capsid protease","volume":"61","author":"Melancon","year":"1987","journal-title":"J. Virol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1006\/jmbi.1998.1817","article-title":"Role of the C-terminal tryptophan residue for the structure-function of the alphavirus capsid protein11Edited by J. Karn","volume":"279","author":"Skoging","year":"1998","journal-title":"J. Mol. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1186\/1743-422X-7-327","article-title":"Functional dissection of the alphavirus capsid protease: Sequence requirements for activity","volume":"7","author":"Thomas","year":"2010","journal-title":"Virol. J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"jcs253237","DOI":"10.1242\/jcs.253237","article-title":"Picornavirus 3C\u2014A protease ensuring virus replication and subverting host responses","volume":"134","author":"Yi","year":"2021","journal-title":"J. Cell Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1016\/j.jmb.2009.02.044","article-title":"Structural and biochemical analysis of human pathogenic Astrovirus serine protease at 2.0 \u00c5 resolution","volume":"387","author":"Speroni","year":"2009","journal-title":"J. Mol. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"16534","DOI":"10.1073\/pnas.1210418109","article-title":"Structural and functional insights into alphavirus polyprotein processing and pathogenesis","volume":"109","author":"Shin","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1007\/s13238-022-00909-3","article-title":"Targeting papain-like protease for broad-spectrum coronavirus inhibition","volume":"13","author":"Yuan","year":"2022","journal-title":"Protein Cell"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3441","DOI":"10.1016\/j.jmb.2017.06.010","article-title":"Structure and function of viral deubiquitinating enzymes","volume":"429","author":"Knaap","year":"2017","journal-title":"J. Mol. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.virusres.2014.01.025","article-title":"Nidovirus papain-like proteases: Multifunctional enzymes with protease, deubiquitinating and deISGylating activities","volume":"194","author":"Mielech","year":"2014","journal-title":"Virus Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1107\/S205979832100509X","article-title":"Structural insights into the interaction of papain-like protease 2 from the alphacoronavirus porcine epidemic diarrhea virus and ubiquitin","volume":"77","author":"Durie","year":"2021","journal-title":"Acta Crystallogr. D Struct. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Cheong, E.Z.K., Quek, J.P., Xin, L., Li, C., Chan, J.Y., Liew, C.W., Mu, Y., Zheng, J., and Luo, D. (2022). Crystal structure of the Rubella virus protease reveals a unique papain-like protease fold. J. Biol. Chem., 298.","DOI":"10.1101\/2022.04.15.488536"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Tchesnokov, E.P., Bailey-Elkin, B.A., Mark, B.L., and G\u00f6tte, M. (2020). Independent inhibition of the polymerase and deubiquitinase activities of the Crimean-Congo Hemorrhagic Fever Virus full-length L-protein. PLoS Neglected Trop. Dis., 14.","DOI":"10.1371\/journal.pntd.0008283"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1099\/jgv.0.000872","article-title":"Assemblins as maturational proteases in herpesviruses","volume":"98","author":"Hinrichs","year":"2017","journal-title":"J. Gen. Virol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"22697","DOI":"10.1074\/jbc.270.39.22697","article-title":"Activation of the Herpes Simplex Virus Type 1 Protease (\u2217)","volume":"270","author":"Hall","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Harrison, J.J.E.K., Tuske, S., Das, K., Ruiz, F.X., Bauman, J.D., Boyer, P.L., DeStefano, J.J., Hughes, S.H., and Arnold, E. (2021). Crystal structure of a Retroviral polyprotein: Prototype Foamy Virus Protease-Reverse Transcriptase (PR-RT). Viruses, 13.","DOI":"10.3390\/v13081495"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Chen, J.-S., Li, H.-C., Lin, S.-I., Yang, C.-H., Chien, W.-Y., Syu, C.-L., and Lo, S.-Y. (2015). Cleavage of dicer protein by I7 protease during vaccinia virus infection. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0120390"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"6335","DOI":"10.1128\/JVI.78.12.6335-6343.2004","article-title":"Role of the I7 protein in proteolytic processing of vaccinia virus membrane and core components","volume":"78","author":"Moss","year":"2004","journal-title":"J. Virol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1006\/viro.2000.0253","article-title":"The effect of mutant peptide cofactors on Adenovirus protease activity and virus infection","volume":"270","author":"Sircar","year":"2000","journal-title":"Virology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"9947","DOI":"10.1128\/JVI.78.18.9947-9953.2004","article-title":"The Vaccinia Virus G1L putative Metalloproteinase is essential for viral replication in vivo","volume":"78","author":"Byrd","year":"2004","journal-title":"J. Virol."},{"key":"ref_68","first-page":"82","article-title":"Pymol: An open-source molecular graphics tool","volume":"40","author":"DeLano","year":"2002","journal-title":"CCP4 Newsl. Protein Crystallogr."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1093\/protein\/11.9.739","article-title":"Protein structure alignment by incremental combinatorial extension (CE) of the optimal path","volume":"11","author":"Shindyalov","year":"1998","journal-title":"Protein Eng."},{"key":"ref_70","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_71","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/s41592-022-01488-1","article-title":"ColabFold: Making protein folding accessible to all","volume":"19","author":"Mirdita","year":"2022","journal-title":"Nat. Methods"},{"key":"ref_72","unstructured":"Lichang, W. (2012). Molecular Dynamics, IntechOpen. Chapter 9."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrd.2018.168","article-title":"Drug repurposing: Progress, challenges and recommendations","volume":"18","author":"Pushpakom","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.jmb.2009.10.048","article-title":"Insights into cleavage specificity from the crystal structure of Foot-and-Mouth Disease Virus 3C protease complexed with a peptide substrate","volume":"395","author":"Zunszain","year":"2010","journal-title":"J. Mol. Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"10319","DOI":"10.1128\/JVI.00787-11","article-title":"Enterovirus 71 and Coxsackievirus A16 3C proteases: Binding to Rupintrivir and their substrates and anti-Hand, Foot, and Mouth Disease Virus drug design","volume":"85","author":"Lu","year":"2011","journal-title":"J. Virol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/j.jmb.2006.06.047","article-title":"An episulfide cation (thiiranium ring) trapped in the active site of HAV 3C proteinase inactivated by peptide-based Ketone inhibitors","volume":"361","author":"Yin","year":"2006","journal-title":"J. Mol. Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.ejmech.2016.11.027","article-title":"Structure-based exploration and exploitation of the S4 subsite of norovirus 3CL protease in the design of potent and permeable inhibitors","volume":"126","author":"Kim","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Hu, X., Morazzani, E., Compton, J.R., Harmon, M., Soloveva, V., Glass, P.J., Garcia, A.D., Marugan, J.J., and Legler, P.M. (2023). In silico screening of inhibitors of the Venezuelan Equine Encephalitis Virus nonstructural protein 2 cysteine protease. Viruses, 15.","DOI":"10.3390\/v15071503"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1021\/acsmedchemlett.3c00359","article-title":"Peptide-to-small molecule: Discovery of non-covalent, active-site inhibitors of \u03b2-Herpesvirus proteases","volume":"14","author":"Yoshida","year":"2023","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.bmcl.2014.12.057","article-title":"Structure-based design and optimization of potent inhibitors of the adenoviral protease","volume":"25","author":"Grosche","year":"2015","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1021\/ml500224t","article-title":"Discovery and structure-based optimization of Adenain inhibitors","volume":"5","author":"Grosche","year":"2014","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1570-9639(03)00024-4","article-title":"Crystallographic structure at 1.6-\u00c5 resolution of the human adenovirus proteinase in a covalent complex with its 11-amino-acid peptide cofactor: Insights on a new fold","volume":"1648","author":"McGrath","year":"2003","journal-title":"Biochim. Et Biophys. Acta (BBA)\u2014Proteins Proteom."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Sinha, S., Tam, B., and Wang, S.M. (2022). Applications of molecular dynamics simulation in protein study. Membranes, 12.","DOI":"10.3390\/membranes12090844"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"D576","DOI":"10.1093\/nar\/gkq901","article-title":"ViralZone: A knowledge resource to understand virus diversity","volume":"39","author":"Hulo","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_86","unstructured":"(2023). UniProt: The Universal Protein Knowledgebase in 2023. Nucleic Acids Res, 51, D523\u2013D531."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1101\/gr.849004","article-title":"WebLogo: A sequence logo generator","volume":"14","author":"Crooks","year":"2004","journal-title":"Genome Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2617","DOI":"10.1016\/j.bmcl.2010.02.063","article-title":"The introduction of P4 substituted 1-methylcyclohexyl groups into Boceprevir\u00ae: A change in direction in the search for a second generation HCV NS3 protease inhibitor","volume":"20","author":"Bennett","year":"2010","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Romano, K.P., Ali, A., Aydin, C., Soumana, D., \u00d6zen, A., Deveau, L.M., Silver, C., Cao, H., Newton, A., and Petropoulos, C.J. (2012). The molecular basis of drug resistance against Hepatitis C Virus NS3\/4A protease inhibitors. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002832"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1021\/cb5006118","article-title":"Structural analysis of Asunaprevir resistance in HCV NS3\/4A protease","volume":"9","author":"Soumana","year":"2014","journal-title":"ACS Chem. Biol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"11850","DOI":"10.1021\/jacs.6b06454","article-title":"Molecular and dynamic mechanism underlying drug resistance in genotype 3 Hepatitis C NS3\/4A protease","volume":"138","author":"Soumana","year":"2016","journal-title":"J. Am. Chem. Soc."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1002\/anie.200906696","article-title":"Induced-fit binding of the macrocyclic noncovalent inhibitor TMC435 to its HCV NS3\/NS4A protease target","volume":"49","author":"Cummings","year":"2010","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1021\/bi501088e","article-title":"Defective hydrophobic sliding mechanism and active site expansion in HIV-1 protease drug resistant variant Gly48Thr\/Leu89Met: Mechanisms for the loss of Saquinavir binding potency","volume":"54","author":"Goldfarb","year":"2015","journal-title":"Biochemistry"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.bbrc.2012.12.127","article-title":"Insights into the mechanism of drug resistance: X-ray structure analysis of multi-drug resistant HIV-1 protease ritonavir complex","volume":"431","author":"Liu","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1021\/bi7018332","article-title":"The contribution of naturally occurring polymorphisms in altering the biochemical and structural characteristics of HIV-1 subtype C protease","volume":"47","author":"Coman","year":"2008","journal-title":"Biochemistry"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1002\/pro.2019","article-title":"Critical differences in HIV-1 and HIV-2 protease specificity for clinical inhibitors","volume":"21","author":"Tie","year":"2012","journal-title":"Protein Sci."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2803","DOI":"10.1016\/S0968-0896(02)00051-2","article-title":"X-ray crystallographic structure of ABT-378 (Lopinavir) bound to HIV-1 protease","volume":"10","author":"Stoll","year":"2002","journal-title":"Bioorganic Med. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"9525","DOI":"10.1128\/JVI.02503-05","article-title":"X-ray crystal structures of Human Immunodeficiency Virus Type 1 protease mutants complexed with Atazanavir","volume":"81","author":"Klei","year":"2007","journal-title":"J. Virol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"12132","DOI":"10.1021\/acsomega.8b01683","article-title":"Drug resistance mutation L76V alters nonpolar interactions at the flap\u2013core interface of HIV-1 protease","volume":"3","author":"Wang","year":"2018","journal-title":"ACS Omega"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1111\/febs.12743","article-title":"Thermodynamic and structural analysis of HIV protease resistance to darunavir\u2014Analysis of heavily mutated patient-derived HIV-1 proteases","volume":"281","author":"Brynda","year":"2014","journal-title":"FEBS J."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"D624","DOI":"10.1093\/nar\/gkx1134","article-title":"The MEROPS database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER database","volume":"46","author":"Rawlings","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"3022","DOI":"10.1093\/molbev\/msab120","article-title":"MEGA11: Molecular Evolutionary Genetics Analysis Version 11","volume":"38","author":"Tamura","year":"2021","journal-title":"Mol. Biol. Evol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"4673","DOI":"10.1093\/nar\/22.22.4673","article-title":"CLUSTAL W: Improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice","volume":"22","author":"Thompson","year":"1994","journal-title":"Nucleic Acids Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"W270","DOI":"10.1093\/nar\/gkz357","article-title":"Evolview v3: A webserver for visualization, annotation, and management of phylogenetic trees","volume":"47","author":"Subramanian","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"102466","DOI":"10.1016\/j.scs.2020.102466","article-title":"BioAider: An efficient tool for viral genome analysis and its application in tracing SARS-CoV-2 transmission","volume":"63","author":"Zhou","year":"2020","journal-title":"Sustain. Cities Soc."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1093\/nar\/gkn072","article-title":"PROMALS3D: A tool for multiple protein sequence and structure alignments","volume":"36","author":"Pei","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","article-title":"Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments","volume":"27","author":"Adzhigirey","year":"2013","journal-title":"J. Comput.-Aided Mol. Des."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.virol.2017.12.020","article-title":"Structure-function insights into chikungunya virus capsid protein: Small molecules targeting capsid hydrophobic pocket","volume":"515","author":"Sharma","year":"2018","journal-title":"Virology"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/1\/225\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:45:15Z","timestamp":1760132715000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/1\/225"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,31]]},"references-count":108,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["molecules29010225"],"URL":"https:\/\/doi.org\/10.3390\/molecules29010225","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,31]]}}}