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While ensitrelvir and nirmatrelvir are approved drugs for treatment, the continuous research and development for new antiviral drugs is necessary to combat the emergence of variants and other related viruses. This study employed structure\u2010 and ligand\u2010based computer\u2010assisted approaches to identify new 3CL\n                    <jats:sup>pro<\/jats:sup>\n                    nonpeptidomimetic inhibitors. Using data from COVID Moonshot, NCATS, and the literature, computational methods such as shape\u2010based, ensemble docking, and machine learning (ML) techniques were developed, achieving robust validation metrics: AUC\u2009=\u200987%, EF\u2009=\u20097, BEDROC\u2009=\u200960% for shape\u2010based; AUC\u2009=\u200987%, EF\u2009=\u20097.03, BEDROC\u2009=\u200962% for ensemble docking, and ACC\u2009=\u200981%, MCC\u2009=\u200962% for ML models, combing Random forest\u2009+\u2009ECFP4 fingerprint. These models were utilized in virtual screening (VS) campaigns using the H3D and ChemBridge libraries, from which six promising hits with IC\n                    <jats:sub>50<\/jats:sub>\n                    values\u2009\u226480\u2009\u00b5M were identified, including LabMol\u2010499 with an IC\n                    <jats:sub>50<\/jats:sub>\n                    of 13.71\u2009\u00b5M and a\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>i<\/jats:sub>\n                    of 21.74\u2009\u00b5M. Moreover, we found that LabMol\u2010499 acts as a noncompetitive, reversible inhibitor of 3CL\n                    <jats:sup>pro<\/jats:sup>\n                    . These findings provide a foundation for hit\u2010to\u2010lead optimization of new nonpeptidomimetic 3CL\n                    <jats:sup>pro<\/jats:sup>\n                    inhibitors.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202501083","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T03:29:45Z","timestamp":1775791785000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structure\u2010 and Ligand\u2010Based Discovery of Novel 3\u2010Chymotrypsin\u2010Like Protease Nonpeptidomimetic Hits"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7040-0865","authenticated-orcid":false,"given":"Sabrina","family":"Silva\u2010Mendon\u00e7a","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Modeling and Drug Design (LabMol) Faculdade de Farm\u00e1cia Universidade Federal de Goi\u00e1s  Goi\u00e2nia Brazil"},{"name":"Center for the Research and Advancement in Fragments and Molecular Targets (CRAFT) School of Pharmaceutical Sciences at Ribeir\u00e3o Preto University of S\u00e3o Paulo  Ribeir\u00e3o Preto Brazil"},{"name":"Center for Excellence in One Health (CESU) Universidade Federal de Goi\u00e1s  Goi\u00e2nia Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8871-5251","authenticated-orcid":false,"given":"Donald","family":"Seanego","sequence":"additional","affiliation":[{"name":"Holistic Drug Discovery and Development Center (H3D) University of Cape Town  Rondebosch South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5032-9363","authenticated-orcid":false,"given":"Christopher","family":"Jurisch","sequence":"additional","affiliation":[{"name":"Holistic Drug Discovery and Development Center (H3D) University of Cape Town  Rondebosch South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0878-9029","authenticated-orcid":false,"given":"Melina","family":"Mottin","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Modeling and Drug Design (LabMol) Faculdade de Farm\u00e1cia Universidade Federal de Goi\u00e1s  Goi\u00e2nia Brazil"},{"name":"Center for the Research and Advancement in Fragments and Molecular Targets (CRAFT) School of Pharmaceutical Sciences at Ribeir\u00e3o Preto University of S\u00e3o Paulo  Ribeir\u00e3o Preto Brazil"},{"name":"Center for Excellence in One Health (CESU) Universidade Federal de Goi\u00e1s  Goi\u00e2nia Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fl\u00e1via","family":"Nader Motta","sequence":"additional","affiliation":[{"name":"Laboratory of Pathogen\u2013Host Interaction (LIPH) Institute of Biological Sciences Universidade de Bras\u00edlia  Bras\u00edlia Brazil"},{"name":"Faculdade de Ceil\u00e2ndia Universidade de Bras\u00edlia  Bras\u00edlia Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatriz","family":"S. 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