{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T04:58:00Z","timestamp":1773982680248,"version":"3.50.1"},"reference-count":31,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,5,1]],"date-time":"2022-05-01T00:00:00Z","timestamp":1651363200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondo di Beneficenza di Intesa Sanpaolo","award":["B\/2020\/0113"],"award-info":[{"award-number":["B\/2020\/0113"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Computation"],"abstract":"<jats:p>Despite the progress of therapeutic approaches for treating COVID-19 infection, the interest in developing effective antiviral agents is still high, due to the possibility of the insurgence of viable SARS-CoV-2-resistant strains. Accordingly, in this article, we describe a computational protocol for identifying possible SARS-CoV-2 Mpro covalent inhibitors. Combining several in silico techniques, we evaluated the potential of the peptide-based scaffold with different warheads as a significant alternative to nitriles and aldehyde electrophilic groups. We rationally designed four potential inhibitors containing difluorstatone and a Michael acceptor as warheads. In silico analysis, based on molecular docking, covalent docking, molecular dynamics simulation, and FEP, indicated that the conceived compounds could act as covalent inhibitors of Mpro and that the investigated warheads can be used for designing covalent inhibitors against serine or cysteine proteases such as SARS-CoV-2 Mpro. Our work enriches the knowledge on SARS-CoV-2 Mpro, providing a novel potential strategy for its inhibition, paving the way for the development of effective antivirals.<\/jats:p>","DOI":"10.3390\/computation10050069","type":"journal-article","created":{"date-parts":[[2022,5,1]],"date-time":"2022-05-01T06:23:08Z","timestamp":1651386188000},"page":"69","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["In Silico Analysis of Peptide-Based Derivatives Containing Bifunctional Warheads Engaging Prime and Non-Prime Subsites to Covalent Binding SARS-CoV-2 Main Protease (Mpro)"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9375-6242","authenticated-orcid":false,"given":"Simone","family":"Brogi","sequence":"first","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8240-6519","authenticated-orcid":false,"given":"Sara","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018\u20132022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3332-3845","authenticated-orcid":false,"given":"Roberta","family":"Ibba","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018\u20132022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8471-0880","authenticated-orcid":false,"given":"Stefania","family":"Butini","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018\u20132022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincenzo","family":"Calderone","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Campiani","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018\u20132022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8313-2417","authenticated-orcid":false,"given":"Sandra","family":"Gemma","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018\u20132022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1152\/physiolgenomics.00089.2020","article-title":"The COVID-19 pandemic: A global health crisis","volume":"52","author":"Pollard","year":"2020","journal-title":"Physiol. 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