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We report a water-aware structure-based protease inhibitor design study. Methods: Our efforts focused on the biological evaluation of small molecule inhibitors that emerged from a conserved water-aware virtual screening campaign of a library of compounds that shared structural or physicochemical properties with known furin inhibitors exhibiting newly recognized binding modes. Results: We identified a novel small-molecule furin protease inhibitor with a 1,3-thiazol-2-ylaminosulfonyl scaffold. Namely, the compound N-[4-(1,3-thiazol-2-ylaminosulfonyl)phenyl]-3-{(E)-5-[(2-methoxyphenyl)methylene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl}propionamide showed an IC50 value of 17.58 \u03bcM, comparable to other published inhibitors. Conclusions: This compound could represent a starting point for the further design and development of non-peptidic, small-molecule furin inhibitors that could assist in furin cleavage studies and coronaviral pathogenesis.<\/jats:p>","DOI":"10.3390\/ph18020273","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T05:34:26Z","timestamp":1739943266000},"page":"273","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Identification of Furin Protease Small-Molecule Inhibitor with a 1,3-Thiazol-2-ylaminosulfonyl Scaffold"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0225-7278","authenticated-orcid":false,"given":"Anja","family":"Kolari\u010d","sequence":"first","affiliation":[{"name":"Laboratory of Physical Chemistry and Chemical Thermodynamics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, SI-2000 Maribor, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5605-3345","authenticated-orcid":false,"given":"Vid","family":"Ravnik","sequence":"additional","affiliation":[{"name":"Laboratory of Physical Chemistry and Chemical Thermodynamics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, SI-2000 Maribor, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2930-2208","authenticated-orcid":false,"given":"Sara","family":"\u0160tumpf Horvat","sequence":"additional","affiliation":[{"name":"Laboratory of Physical Chemistry and Chemical Thermodynamics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, SI-2000 Maribor, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6083-5024","authenticated-orcid":false,"given":"Marko","family":"Juki\u010d","sequence":"additional","affiliation":[{"name":"Laboratory of Physical Chemistry and Chemical Thermodynamics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, SI-2000 Maribor, Slovenia"},{"name":"Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska, Glagolja\u0161ka ulica 8, SI-6000 Koper, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urban","family":"Bren","sequence":"additional","affiliation":[{"name":"Laboratory of Physical Chemistry and Chemical Thermodynamics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, SI-2000 Maribor, Slovenia"},{"name":"Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska, Glagolja\u0161ka ulica 8, SI-6000 Koper, Slovenia"},{"name":"Institute of Environmental Protection and Sensors, Beloruska ulica 7, SI-2000 Maribor, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1038\/nrm934","article-title":"Furin at the cutting edge: From protein traffic to embryogenesis and disease","volume":"3","author":"Thomas","year":"2002","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e1073","DOI":"10.1002\/cti2.1073","article-title":"Furin-mediated protein processing in infectious diseases and cancer","volume":"8","author":"Braun","year":"2019","journal-title":"Clin. Transl. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1021\/acs.jmedchem.1c00518","article-title":"Why all the fury over furin?","volume":"65","author":"Osman","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Thomas, G., Couture, F., and Kwiatkowska, A. (2022). The Path to therapeutic furin inhibitors: From Yeast Pheromones to SARS-CoV-2. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23073435"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"11727","DOI":"10.1073\/pnas.2003138117","article-title":"Cell entry mechanisms of SARS-CoV-2","volume":"117","author":"Shang","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1111\/1348-0421.12945","article-title":"Proteolytic activation of SARS-CoV-2 spike protein","volume":"66","author":"Takeda","year":"2021","journal-title":"Microbiol. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.cell.2020.02.058","article-title":"Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein","volume":"181","author":"Walls","year":"2020","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1038\/s41564-021-00931-x","article-title":"How SARS-CoV-2 makes the cut","volume":"6","author":"Hoffmann","year":"2021","journal-title":"Nat. Microbiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"104742","DOI":"10.1016\/j.antiviral.2020.104742","article-title":"The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade","volume":"176","author":"Coutard","year":"2020","journal-title":"Antiviral Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"36788","DOI":"10.1074\/jbc.M400484200","article-title":"Inhibition of furin by polyarginine-containing peptides: Nanomolar inhibition by nona-D-arginine","volume":"279","author":"Kacprzak","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ivachtchenko, A.V., Khvat, A.V., and Shkil, D.O. (2024). Development and Prospects of Furin Inhibitors for Therapeutic Applications. Int. J. Mol. 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Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/j.chembiol.2022.02.001","article-title":"A highly selective, cell-permeable furin inhibitor BOS-318 rescues key features of cystic fibrosis airway disease","volume":"29","author":"Douglas","year":"2022","journal-title":"Cell Chem. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Kralj, S., Juki\u010d, M., and Bren, U. (2022). Comparative analyses of medicinal chemistry and cheminformatics filters with accessible implementation in Konstanz information miner (KNIME). Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105727"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3094","DOI":"10.1021\/acs.jcim.7b00443","article-title":"Identification of conserved water sites in protein structures for drug design","volume":"57","author":"Jukic","year":"2017","journal-title":"J. Chem. Inf. Model."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1021\/acsmedchemlett.9b00651","article-title":"ProBiS H2O MD approach for identification of conserved water sites in protein structures for drug design","volume":"11","author":"Konc","year":"2020","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5204","DOI":"10.1021\/acs.jcim.3c00558","article-title":"Identifying Metal Binding Sites in Proteins Using Homologous Structures, the MADE Approach","volume":"63","author":"Ravnik","year":"2023","journal-title":"J. Chem. Inf. Model."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2302","DOI":"10.1093\/nar\/gki524","article-title":"TM-align: A protein structure alignment algorithm based on the TM-score","volume":"33","author":"Zhang","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_21","first-page":"226","article-title":"A density-based algorithm for discovering clusters in large spatial databases with noise","volume":"96","author":"Ester","year":"1996","journal-title":"kdd"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6582","DOI":"10.1021\/jm300687e","article-title":"Directory of useful decoys, enhanced (DUD-E): Better ligands and decoys for better benchmarking","volume":"55","author":"Mysinger","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.4155\/fmc.10.237","article-title":"Observations on screening-based research and some concerning trends in the literature","volume":"2","author":"Baell","year":"2010","journal-title":"Future Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4186","DOI":"10.1021\/acsomega.3c04749","article-title":"Structure\u2013Activity Relationship Study and Design Strategies of Hydantoin, Thiazolidinedione, and Rhodanine-Based Kinase Inhibitors: A Two-Decade Review","volume":"9","author":"Naufal","year":"2024","journal-title":"ACS omega"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1080\/17460441.2017.1388370","article-title":"Recent developments with rhodanine as a scaffold for drug discovery","volume":"12","author":"Kaminskyy","year":"2017","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1177\/1087057112452137","article-title":"Small-molecule inhibitors of the protein methyltransferase SET7\/9 identified in a high-throughput screen","volume":"17","author":"Francis","year":"2012","journal-title":"J. Biomol. Screen."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ruiz-Carmona, S., Alvarez-Garcia, D., Foloppe, N., Garmendia-Doval, A.B., Juhos, S., Schmidtke, P., Barril, X., Hubbard, R.E., and Morley, S.D. (2014). rDock: A fast, versatile and open source program for docking ligands to proteins and nucleic acids. PLoS Comput. Biol., 10.","DOI":"10.1371\/journal.pcbi.1003571"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1021\/jm061277y","article-title":"Diverse, High-Quality Test Set for the Validation of Protein\u2212Ligand Docking Performance","volume":"50","author":"Hartshorn","year":"2007","journal-title":"J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1023\/B:JCAM.0000035199.48747.1e","article-title":"Validation of an empirical RNA-ligand scoring function for fast flexible docking using RiboDock\u00ae","volume":"18","author":"Morley","year":"2004","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1007\/s10822-019-00212-0","article-title":"Extensive benchmark of rDock as a peptide-protein docking tool","volume":"33","author":"Soler","year":"2019","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"501","DOI":"10.3390\/encyclopedia3020035","article-title":"Molecular filters in medicinal chemistry","volume":"3","author":"Kralj","year":"2023","journal-title":"Encyclopedia"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/2\/273\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:37:46Z","timestamp":1760027866000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/2\/273"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,19]]},"references-count":31,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["ph18020273"],"URL":"https:\/\/doi.org\/10.3390\/ph18020273","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,19]]}}}