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The 3-chymotrypsin-like protease (3CLpro) is a validated molecular target for COVID-19, and it is key for developing potent and selective inhibitors for inhibiting viral replication of SARS-CoV-2. In this review, we discuss structural relationships and diverse subsites of 3CLpro, shedding light on the pivotal role of dimerization and active site architecture in substrate recognition and catalysis. Our analysis of bioinformatics and other published studies motivated us to investigate a novel catalytic mechanism for the SARS-CoV-2 polyprotein cleavage by 3CLpro, centering on the triad mechanism involving His41-Cys145-Asp187 and its indispensable role in viral replication. Our hypothesis is that Asp187 may participate in modulating the pKa of the His41, in which catalytic histidine may act as an acid and\/or a base in the catalytic mechanism. Recognizing Asp187 as a crucial component in the catalytic process underscores its significance as a fundamental pharmacophoric element in drug design. Next, we provide an overview of both covalent and non-covalent inhibitors, elucidating advancements in drug development observed in preclinical and clinical trials. By highlighting various chemical classes and their pharmacokinetic profiles, our review aims to guide future research directions toward the development of highly selective inhibitors, underscore the significance of 3CLpro as a validated therapeutic target, and propel the progression of drug candidates through preclinical and clinical phases.<\/jats:p>","DOI":"10.3390\/v16060844","type":"journal-article","created":{"date-parts":[[2024,5,27]],"date-time":"2024-05-27T10:14:07Z","timestamp":1716804847000},"page":"844","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["3-Chymotrypsin-like Protease (3CLpro) of SARS-CoV-2: Validation as a Molecular Target, Proposal of a Novel Catalytic Mechanism, and Inhibitors in Preclinical and Clinical Trials"],"prefix":"10.3390","volume":"16","author":[{"given":"Vitor Martins de Freitas","family":"Amorim","sequence":"first","affiliation":[{"name":"Department of Microbiology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 5508-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8420-4889","authenticated-orcid":false,"given":"Eduardo Pereira","family":"Soares","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 5508-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7072-4846","authenticated-orcid":false,"given":"Anielle Salviano de Almeida","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 5508-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6897-2955","authenticated-orcid":false,"given":"Davi Gabriel Salustiano","family":"Merighi","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 5508-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5284-4630","authenticated-orcid":false,"given":"Robson Francisco","family":"de Souza","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 5508-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5664-8055","authenticated-orcid":false,"given":"Cristiane Rodrigues","family":"Guzzo","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 5508-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anacleto Silva de","family":"Souza","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 5508-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2350002","DOI":"10.1142\/S2737599423500020","article-title":"Lifting Scheme-Based Wavelet Transform Method for Improved Genomic Classification and Sequence Analysis of Coronavirus","volume":"10","author":"Kar","year":"2023","journal-title":"Innov. 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