{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T19:32:18Z","timestamp":1778787138111,"version":"3.51.4"},"reference-count":108,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The recent global spread of the SARS-CoV-2 pathogen, which causes COVID-19, and its rapid mutation, requires the fast development of effective preventive and treatment measures. According to WHO reports, over 778 million confirmed cases of COVID-19 have been reported, including approximately 7 million deaths. The androgen-regulated cell-surface serine protease TMPRSS2 interacts with the SARS-CoV-2 spike protein. Therefore, directly inhibiting TMPRSS2 will negatively impact the activation of coronaviruses and, consequently, disease progression. That is why TMPRSS2 is a very important target in current drug discovery. On the other hand, it is known that C60 fullerene (a nearly spherical molecule consisting of 60 carbon atoms) exhibits activity against various protein targets. Here, for the first time, the potential binding of C60 fullerene with TMPRSS2 was investigated using different computer simulation methods, including p2Rank, PCA, gmx_MMPBSA analysis, molecular docking, and molecular dynamics simulations. As a result, four potential binding pockets on the TMPRSS2 surface that could interact with C60 fullerene were identified. Among all \u201cC60 fullerene-TMPRSS2\u201d complexes, one was selected as the most promising binding site based on the results of computational modeling evaluations. This opens up the prospect of creating new anticoronavirus drugs based on these carbon nanoparticles.<\/jats:p>","DOI":"10.3390\/molecules30234586","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T16:47:37Z","timestamp":1764780457000},"page":"4586","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["In Silico Analysis of C60 Fullerene Interaction with TMPRSS2: Toward Novel COVID-19 Prevention Approaches"],"prefix":"10.3390","volume":"30","author":[{"given":"Vasyl","family":"Hurmach","sequence":"first","affiliation":[{"name":"Institute of Molecular Biology and Genetics, National Academy of Science (NAS) of Ukraine, 03143 Kyiv, Ukraine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Viacheslav","family":"Karaushu","sequence":"additional","affiliation":[{"name":"Taras Shevchenko National University of Kyiv, 01601 Kyiv, Ukraine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Svitlana","family":"Prylutska","sequence":"additional","affiliation":[{"name":"National University of Life and Environmental Science of Ukraine, 03041 Kyiv, Ukraine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0771-7808","authenticated-orcid":false,"given":"Zinaida","family":"Klestova","sequence":"additional","affiliation":[{"name":"The Institute for Medical Virology and Epidemiology of Viral Diseases, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergiy","family":"Vyzhva","sequence":"additional","affiliation":[{"name":"Taras Shevchenko National University of Kyiv, 01601 Kyiv, Ukraine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuriy","family":"Prylutskyy","sequence":"additional","affiliation":[{"name":"Taras Shevchenko National University of Kyiv, 01601 Kyiv, Ukraine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9315-4863","authenticated-orcid":false,"given":"Uwe","family":"Ritter","sequence":"additional","affiliation":[{"name":"Technical University of Ilmenau, 98693 Ilmenau, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9315-4188","authenticated-orcid":false,"given":"Vasil","family":"Garamus","sequence":"additional","affiliation":[{"name":"Helmholtz-Zentrum Hereon, 21502 Geesthacht, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"ref_1","first-page":"1843","article-title":"Detection of SARS-CoV-2 in Different Types of Clinical Specimens","volume":"323","author":"Wang","year":"2020","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1016\/j.cell.2020.08.021","article-title":"Emerging Pandemic Diseases: How We Got to COVID-19","volume":"182","author":"Morens","year":"2020","journal-title":"Cell"},{"key":"ref_3","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_4","doi-asserted-by":"crossref","unstructured":"Chung, Y.-S., Lam, C.-Y., Tan, P.-H., Tsang, H.-F., and Wong, S.-C.C. (2024). Comprehensive Review of COVID-19: Epidemiology, Pathogenesis, Advancement in Diagnostic and Detection Techniques, and Post-Pandemic Treatment Strategies. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25158155"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e10","DOI":"10.54724\/lc.2022.e10","article-title":"Global, regional, and national incidence and mortality of COVID-19 in 237 countries and territories, January 2022: A systematic analysis for World Health Organization COVID-19 Dashboard","volume":"2","author":"Kim","year":"2022","journal-title":"Life Cycle"},{"key":"ref_6","unstructured":"(2025, November 26). Available online: https:\/\/data.who.int\/dashboards\/covid19\/deaths?n=c."},{"key":"ref_7","unstructured":"(2025, November 26). Available online: https:\/\/covid19.who.int."},{"key":"ref_8","unstructured":"(2025, November 26). Available online: https:\/\/www.elifecycle.org\/archive\/view_article?pid=lc-2-0-10."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Payne, S. (2017). Family Coronaviridae. Viruses, Academic Press.","DOI":"10.1016\/B978-0-12-803109-4.00017-9"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Coronaviridae Study Group of the International Committee on Taxonomy of Viruses (2020). The species Severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol., 5, 536\u2013544.","DOI":"10.1038\/s41564-020-0695-z"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s44149-021-00005-9","article-title":"The taxonomy, host range and pathogenicity of coronaviruses and other viruses in the Nidovirales order","volume":"1","author":"Zhou","year":"2021","journal-title":"Anim. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"001843","DOI":"10.1099\/jgv.0.001843","article-title":"ICTV Virus Taxonomy Profile: Coronaviridae 2023","volume":"104","author":"Woo","year":"2023","journal-title":"J. Gen. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"115810","DOI":"10.1016\/j.microc.2025.115810","article-title":"Investigation of interaction between immobilized SARS-CoV-2 nucleoprotein and monoclonal antibodies by cyclic voltammetry based electrochemical immunosensor","volume":"219","author":"Karnitskaya","year":"2025","journal-title":"Microchem. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1038\/s41423-020-0374-2","article-title":"Fusion mechanism of 2019-nCoV and fusion inhibitors targeting HR1 domain in spike protein","volume":"17","author":"Xia","year":"2020","journal-title":"Cell. Mol. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41586-020-2012-7","article-title":"A pneumonia outbreak associated with a new coronavirus of probable bat origin","volume":"579","author":"Zhou","year":"2020","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1007\/s10096-020-03899-4","article-title":"The genetic sequence, origin, and diagnosis of SARS-CoV-2","volume":"39","author":"Wang","year":"2020","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/j.jiph.2021.04.007","article-title":"COVID-19 versus SARS: A comparative review","volume":"14","author":"Keshta","year":"2021","journal-title":"J. Infect. Public. Health"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1007\/s10311-020-01151-1","article-title":"Tracing the origins of SARS-COV-2 in coronavirus phylogenies: A review","volume":"19","author":"Sallard","year":"2021","journal-title":"Environ. Chem. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Cicaloni, V., Costanti, F., Pasqui, A., Bianchini, M., Niccolai, N., and Bongini, P. (2022). A Bioinformatics Approach to Investigate Structural and Non-Structural Proteins in Human Coronaviruses. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.891418"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e70050","DOI":"10.1002\/pro.70050","article-title":"Torsional twist of the SARS-CoV and SARS-CoV-2 SUD-N and SUD-M domains","volume":"34","author":"Minasov","year":"2025","journal-title":"Protein Sci."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Hoenigsperger, H., Sivarajan, R., and Sparrer, K.M. (2024). Differences and similarities between innate immune evasion strategies of human coronaviruses. Curr. Opin. Microbiol., 79.","DOI":"10.1016\/j.mib.2024.102466"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2738","DOI":"10.1007\/s00018-004-4242-5","article-title":"Angiotensin-converting enzyme 2: A functional receptor for SARS coronavirus","volume":"61","author":"Kuhn","year":"2004","journal-title":"Cell Mol. Life Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1136\/jclinpath-2020-206987","article-title":"Gene of the month: TMPRSS2 (transmembrane serine protease 2)","volume":"73","author":"Thunders","year":"2020","journal-title":"J. Clin. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1016\/j.mayocp.2020.06.018","article-title":"Targeting TMPRSS2 in SARS-CoV-2 Infection","volume":"95","author":"Baughn","year":"2020","journal-title":"Mayo Clin. Proc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e105114","DOI":"10.15252\/embj.20105114","article-title":"SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells","volume":"39","author":"Lukassen","year":"2020","journal-title":"EMBO J."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Gkogkou, E., Barnasas, G., Vougas, K., and Trougakos, I.P. (2020). Expression profiling meta-analysis of ACE2 and TMPRSS2, the putative anti-inflammatory receptor and priming protease of SARS-CoV-2 in human cells, and identification of putative modulators. Redox Biol., 36.","DOI":"10.1016\/j.redox.2020.101615"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Grisard, H.B.D.S., Sch\u00f6rner, M.A., Barazzetti, F.H., Wachter, J.K., Valmorbida, M., Wagner, G., Fongaro, G., and Bazzo, M.L. (2024). ACE2 and TMPRSS2 expression in patients before, during, and after SARS-CoV-2 infection. Front. Cell. Infect. Microbiol., 14.","DOI":"10.3389\/fcimb.2024.1355809"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/s41586-020-2179-y","article-title":"Structural basis of receptor recognition by SARS-CoV-2","volume":"581","author":"Shang","year":"2020","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/B978-0-12-385504-6.00001-4","article-title":"Membrane-anchored serine proteases in health and disease","volume":"99","author":"Antalis","year":"2011","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5586","DOI":"10.1128\/JVI.00015-16","article-title":"Identification of the Fusion Peptide-Containing Region in Betacoronavirus Spike Glycoproteins","volume":"90","author":"Ou","year":"2016","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Dong, M., Zhang, J., Ma, X., Tan, J., Chen, L., Liu, S., Xin, Y., and Zhuang, L. (2020). ACE2, TMPRSS2 distribution and extrapulmonary organ injury in patients with COVID-19. Biomed. Pharmacother., 131.","DOI":"10.1016\/j.biopha.2020.110678"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3977","DOI":"10.2147\/IDR.S270543","article-title":"Multiple Expression Assessments of ACE2 and TMPRSS2 SARS-CoV-2 Entry Molecules in the Urinary Tract and Their Associations with Clinical Manifestations of COVID-19","volume":"13","author":"Ren","year":"2020","journal-title":"Infect. Drug Resist."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Williams, T.L., Strachan, G., Macrae, R.G.C., Kuc, R.E., Nyimanu, D., Paterson, A.L., Sinha, S., Maguire, J.J., and Davenport, A.P. (2021). Differential expression in humans of the viral entry receptor ACE2 compared with the short delta ACE2 isoform lacking SARS-CoV-2 binding sites. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-03731-9"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4122","DOI":"10.1128\/JVI.02232-10","article-title":"Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response","volume":"85","author":"Glowacka","year":"2011","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5502","DOI":"10.1128\/JVI.00128-13","article-title":"The spike protein of the emerging betacoronavirus EMC uses a novel coronavirus receptor for entry, can be activated by TMPRSS2, and is targeted by neutralizing antibodies","volume":"87","author":"Gierer","year":"2013","journal-title":"J. Virol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.antiviral.2015.01.011","article-title":"Protease inhibitors targeting coronavirus and filovirus entry","volume":"116","author":"Zhou","year":"2015","journal-title":"Antivir. Res."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Chen, V.H.E., Tay, J.K., Gurung, R., Nair, S., Tay, D.J.W., Tan, K.S., Foo, R.S.Y., and Tambyah, P.A. (2025). ACE2 and TMPRSS2 gene expression is reduced acutely in SARS-CoV-2 patients but returns to normal with recovery. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-96279-x"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5638","DOI":"10.1080\/07391102.2020.1792346","article-title":"Computer-aided screening for potential TMPRSS2 inhibitors: A combination of pharmacophore modeling, molecular docking and molecular dynamics simulation approaches","volume":"39","author":"Idris","year":"2021","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1158\/2159-8290.CD-20-0451","article-title":"TMPRSS and COVID-19: Serendipity or Opportunity for Intervention?","volume":"10","author":"Stopsack","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1111\/jop.13621","article-title":"SARS-CoV-2 Entry Factors ACE2, TMPRSS2 and FURIN in Salivary Glands From Primary Sj\u00f6gren\u2019s Disease","volume":"54","author":"Felix","year":"2025","journal-title":"J. Oral. Pathol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.biochi.2017.07.016","article-title":"TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections","volume":"142","author":"Shen","year":"2017","journal-title":"Biochimie"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3147","DOI":"10.1111\/bph.15092","article-title":"Potential therapeutic targets and promising drugs for combating SARS-CoV-2","volume":"177","author":"Zhou","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/s41392-022-01084-x","article-title":"TMPRSS2, a novel host-directed drug target against SARS-CoV-2","volume":"7","author":"Keller","year":"2022","journal-title":"Sig. Transduct. Target. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"110218","DOI":"10.1016\/j.virol.2024.110218","article-title":"TMPRSS2-specific antisense oligonucleotides inhibit host cell entry of emerging viruses","volume":"600","author":"Nowak","year":"2024","journal-title":"Virology"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Xia, Q., Liu, X., and Huang, H. (2025). Host proteases: Key regulators in viral infection and therapeutic targeting. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1671173"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.csbj.2020.12.035","article-title":"Spontaneous binding of potential COVID-19 drugs (Camostat and Nafamostat) to human serine protease TMPRSS2","volume":"19","author":"Zhu","year":"2021","journal-title":"Comput. Struct. Biotechnol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"101","DOI":"10.4274\/MMJ.galenos.2025.40460","article-title":"TMPRSS2: A Key Host Factor in SARS-CoV-2 Infection and Potential Therapeutic Target","volume":"26","author":"Koyou","year":"2025","journal-title":"Medeni. Med. J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.2217\/nnm-2020-0117","article-title":"Application of nanomaterials in treatment, anti-infection and detection of coronaviruses","volume":"15","author":"Nikaeen","year":"2020","journal-title":"Nanomedicine"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"6606","DOI":"10.1039\/D0SC02658A","article-title":"Carbon-based antiviral nanomaterials: Graphene, C-dots, and fullerenes. A perspective","volume":"11","author":"Innocenzi","year":"2020","journal-title":"Chem. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1107\/S2053273313034220","article-title":"Viruses and fullerenes\u2014Symmetry as a common thread?","volume":"70","author":"Dechant","year":"2014","journal-title":"Acta Crystallogr. A Found. Adv."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1007\/s12668-020-00762-w","article-title":"Evaluation of the biocompatibility of water-soluble pristine C60 fullerenes in rabbit","volume":"10","author":"Halenova","year":"2020","journal-title":"BioNanoSci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.mattod.2017.03.017","article-title":"Fullerene: Biomedical engineers get to revisit an old friend","volume":"20","author":"Goodarzi","year":"2017","journal-title":"Mater. Today"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1039\/C9CC08400B","article-title":"Direct arylation of C60Cl6 and C70Cl8 with carboxylic acids: A synthetic avenue to water-soluble fullerene derivatives with promising antiviral activity","volume":"56","author":"Kraevaya","year":"2020","journal-title":"Chem. Commun."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Di Costanzo, L., and Geremia, S. (2020). Atomic Details of Carbon-Based Nanomolecules Interacting with Proteins. Molecules, 25.","DOI":"10.3390\/molecules25153555"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"6510","DOI":"10.1021\/ja00068a006","article-title":"Synthesis of a fullerene derivative for the inhibition of HIV enzymes","volume":"115","author":"Sijbesma","year":"1993","journal-title":"J. Am. Chem. Soc."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3615","DOI":"10.1016\/j.bmcl.2005.05.069","article-title":"Anti-HIV properties of cationic fullerene derivatives","volume":"15","author":"Marchesan","year":"2005","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4565","DOI":"10.1016\/j.bmcl.2016.08.086","article-title":"Novel fullerene derivatives as dual inhibitors of Hepatitis C virus NS5B polymerase and NS3\/4A protease","volume":"26","author":"Kataoka","year":"2016","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1186\/s11671-023-03895-5","article-title":"The potential of carbon-based nanomaterials in hepatitis C virus treatment: A review of carbon nanotubes, dendrimers and fullerenes","volume":"18","author":"Nader","year":"2023","journal-title":"Discov. Nano"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Hurmach, V.V., Platonov, M.O., Prylutska, S.V., Scharff, P., Prylutskyy, Y.I., and Ritter, U. (2021). C60 fullerene against SARS-CoV-2 coronavirus: An in silico insight. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-97268-6"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/978-3-030-85109-5_10","article-title":"Anticoronavirus activity of water-soluble pristine C60 fullerenes: In vitro and In Silico screenings","volume":"Volume 1352","author":"Asea","year":"2021","journal-title":"Coronavirus Therapeutics\u2014Volume I"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Kraevaya, O.A., Bolshakova, V.S., Slita, A.V., Esaulkova, I.L., Zhilenkov, A.V., Mikhalsky, M.G., Sinegubova, E.O., Voronov, I.I., Peregudov, A.S., and Shestakov, A.F. (2025). Buckyballs to fight pandemic: Water-soluble fullerene derivatives with pendant carboxylic groups emerge as a new family of promising SARS-CoV-2 inhibitors. Bioorg. Chem., 154.","DOI":"10.1016\/j.bioorg.2024.108097"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1038\/s41589-022-01059-7","article-title":"Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation","volume":"18","author":"Fraser","year":"2022","journal-title":"Nat. Chem. Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1007\/s00894-009-0454-9","article-title":"Solvent accessible surface area approximations for rapid and accurate protein structure prediction","volume":"15","author":"Durham","year":"2009","journal-title":"J. Mol. Model."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1021\/ct500867u","article-title":"Identification of protein-ligand binding sites by the level-set variational implicit-solvent approach","volume":"11","author":"Guo","year":"2015","journal-title":"J. Chem. Theory Comput."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Wettstein, L., Kirchhoff, F., and M\u00fcnch, J. (2022). The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031351"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.1038\/s41467-024-46394-6","article-title":"Molecular basis of TMPRSS2 recognition by Paeniclostridium sordellii hemorrhagic toxin","volume":"15","author":"Zhou","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"6636","DOI":"10.1038\/s41467-025-62023-2","article-title":"The crystal structure of coronavirus RBD-TMPRSS2 complex provides basis for the discovery of therapeutic antibodies","volume":"16","author":"Zhao","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Shi, Y.-H., Shen, J.-X., Tao, Y., Xia, Y.-L., Zhang, Z.-B., Fu, Y.-X., Zhang, K.-Q., and Liu, S.-Q. (2025). Dissecting the Binding Affinity of Anti-SARS-CoV-2 Compounds to Human Transmembrane Protease, Serine 2: A Computational Study. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26020587"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s00249-023-01695-4","article-title":"Inhibitor design for TMPRSS2: Insights from computational analysis of its backbone hydrogen bonds using a simple descriptor","volume":"53","author":"Ugrani","year":"2024","journal-title":"Eur. Biophys. J."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Sgrignani, J., and Cavalli, A. (2021). Computational Identification of a Putative Allosteric Binding Pocket in TMPRSS2. Front. Mol. Biosci., 8.","DOI":"10.3389\/fmolb.2021.666626"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1098\/rsif.2011.0584","article-title":"Flexibility and binding affinity in protein-ligand, protein-protein and multi-component protein interactions: Limitations of current computational approaches","volume":"9","author":"Tuffery","year":"2012","journal-title":"J. R. Soc. Interface."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2276","DOI":"10.1038\/s41467-017-02258-w","article-title":"Protein conformational flexibility modulates kinetics and thermodynamics of drug binding","volume":"8","author":"Amaral","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"E3416","DOI":"10.1073\/pnas.1711490115","article-title":"Exploring the structural origins of cryptic sites on proteins","volume":"115","author":"Beglov","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cbpa.2018.05.003","article-title":"Cryptic binding sites on proteins: Definition, detection, and druggability","volume":"44","author":"Vajda","year":"2018","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"11232","DOI":"10.1021\/la9022807","article-title":"Hydration and dispersion of C60 in aqueous systems: The nature of water-fullerene interactions","volume":"25","author":"Labille","year":"2009","journal-title":"Langmuir"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Marforio, T.D., Calza, A., Mattioli, E.J., Zerbetto, F., and Calvaresi, M. (2021). Dissecting the Supramolecular Dispersion of Fullerenes by Proteins\/Peptides: Amino Acid Ranking and Driving Forces for Binding to C60. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111567"},{"key":"ref_78","unstructured":"(2025, November 26). Available online: https:\/\/www.pymol.org\/."},{"key":"ref_79","unstructured":"(2025, November 26). Available online: https:\/\/matplotlib.org\/."},{"key":"ref_80","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_81","doi-asserted-by":"crossref","first-page":"W375","DOI":"10.1093\/nar\/gkm216","article-title":"MolProbity: All-atom contacts and structure validation for proteins and nucleic acids","volume":"35","author":"Davis","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1002\/pro.3330","article-title":"MolProbity: More and better reference data for improved all-atom structure validation","volume":"27","author":"Williams","year":"2018","journal-title":"Protein Sci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1002\/wcms.74","article-title":"Recent Developments and Applications of the CHARMM force fields","volume":"2","author":"Zhu","year":"2012","journal-title":"Wiley Interdiscip. Rev. Comput. Mol. Sci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.bbagen.2014.08.004","article-title":"CHARMM additive and polarizable force fields for biophysics and computer-aided drug design","volume":"1850","author":"Vanommeslaeghe","year":"2015","journal-title":"Biochim. Biophys. Acta."},{"key":"ref_85","unstructured":"(2025, November 26). Available online: https:\/\/mackerell.umaryland.edu\/charmm_ff.shtml."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13321-018-0285-8","article-title":"P2Rank: Machine learning based tool for rapid and accurate prediction of ligand binding sites from protein structure","volume":"10","author":"Hoksza","year":"2018","journal-title":"J. Cheminform."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1002\/jcc.540160303","article-title":"The double cubic lattice method: Efficient approaches to numerical integration of surface area and volume and to dot surface contouring of molecular assemblies","volume":"16","author":"Eisenhaber","year":"1995","journal-title":"Comp. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1021\/ci025584y","article-title":"The Chemistry Development Kit (CDK): An open-source Java library for Chemo- and Bioinformatics","volume":"43","author":"Steinbeck","year":"2003","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s13321-017-0220-4","article-title":"The Chemistry Development Kit (CDK) v2.0: Atom typing, depiction, molecular formulas, and substructure searching","volume":"9","author":"Willighagen","year":"2017","journal-title":"J. Cheminform."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.2174\/092986611797642788","article-title":"Improved prediction of protein ligand-binding sites using random forests","volume":"18","author":"Qiu","year":"2011","journal-title":"Protein Pept. Lett."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Chen, P., Huang, J.Z., and Gao, X. (2014). LigandRFs: Random forest ensemble to identify ligand-binding residues from sequence information alone. BMC Bioinform., 15.","DOI":"10.1186\/1471-2105-15-S15-S4"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1758-2946-3-33","article-title":"Open Babel: An open chemical toolbox","volume":"3","author":"Banck","year":"2011","journal-title":"J. Cheminform."},{"key":"ref_93","unstructured":"(2025, November 26). Available online: https:\/\/www.swissdock.ch\/."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1002\/jcc.24249","article-title":"Attracting cavities for docking. Replacing the rough energy landscape of the protein by a smooth attracting landscape","volume":"37","author":"Zoete","year":"2016","journal-title":"J. Comput. Chem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"3925","DOI":"10.1021\/acs.jcim.3c00054","article-title":"Attracting Cavities 2.0: Improving the Flexibility and Robustness for Small-Molecule Docking","volume":"63","author":"Goullieux","year":"2023","journal-title":"J. Chem. Inf. Model."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.1002\/jcc.21816","article-title":"SwissParam: A fast force field generation tool for small organic molecules","volume":"32","author":"Zoete","year":"2011","journal-title":"J. Comput. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"6469","DOI":"10.1021\/acs.jcim.3c01053","article-title":"SwissParam 2023: A Modern Web-Based Tool for Efficient Small Molecule Parametrization","volume":"63","author":"Bugnon","year":"2023","journal-title":"J. Chem. Inf. Model."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1002\/prot.340170408","article-title":"Essential dynamics of proteins","volume":"17","author":"Amadei","year":"1993","journal-title":"Proteins"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/S1574-1400(06)02013-5","article-title":"Principal Components Analysis: A Review of its Application on Molecular Dynamics Data","volume":"2","author":"Stein","year":"2006","journal-title":"Annu. Rep. Comput. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/j.bpj.2011.12.053","article-title":"Exploring the Energy Landscapes of Protein Folding Simulations with Bayesian Computation","volume":"102","author":"Burkoff","year":"2012","journal-title":"Biophys. J."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1002\/prot.21344","article-title":"Free energy landscape of a biomolecule in dihedral principal component space: Sampling convergence and correspondence between structures and minima","volume":"67","author":"Maisuradze","year":"2007","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_103","unstructured":"Meshulam, L., Gauthier, J.L., Brody, C.D., Tank, D.W., and Bialek, W. (2021). Successes and failures of simple statistical physics models for a network of real neurons. arXiv."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S0006-3495(03)74462-2","article-title":"Protocol for MM\/PBSA molecular dynamics simulations of proteins","volume":"85","author":"Fogolari","year":"2003","journal-title":"Biophys. J."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1517\/17460441.2015.1032936","article-title":"The MM\/PBSA and MM\/GBSA methods to estimate ligand-binding affinities","volume":"10","author":"Genheden","year":"2015","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"e04944","DOI":"10.1016\/j.heliyon.2020.e04944","article-title":"Application of per-residue energy decomposition to identify the set of amino acids critical for in silico prediction of COX-2 inhibitory activity","volume":"7","author":"Chaudhary","year":"2020","journal-title":"Heliyon"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"6281","DOI":"10.1021\/acs.jctc.1c00645","article-title":"gmx_MMPBSA: A New Tool to Perform End-State Free Energy Calculations with GROMACS","volume":"17","author":"Valiente","year":"2021","journal-title":"J. Chem. Theory Comput."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"3314","DOI":"10.1021\/ct300418h","article-title":"MMPBSA.py: An Efficient Program for End-State Free Energy Calculations","volume":"8","author":"Miller","year":"2012","journal-title":"J. Chem. Theory Comput."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/23\/4586\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T16:48:45Z","timestamp":1764780525000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/23\/4586"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,28]]},"references-count":108,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["molecules30234586"],"URL":"https:\/\/doi.org\/10.3390\/molecules30234586","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,28]]}}}