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Using a fragment-based multilevel virtual screening strategy, 15 hit compounds were identified and subsequently synthesized. Among them, A5 (IC50 = 1.05 \u03bcM), A6 (IC50 = 1.08 \u03bcM), and A9 (IC50 = 0.154 \u03bcM) demonstrated potent SARS-CoV-2 Mpro inhibition comparable to or slightly weaker than WU-04. Antiviral activity evaluations revealed that compound A9 exhibited the strongest antiviral activity with an EC50 value of 0.18 \u03bcM, quite comparable to the marketed drug Nirmatrelvir (EC50 = 0.123 \u03bcM) and inferior to WU-04 (EC50 = 0.042 \u03bcM). Molecular dynamics simulations elucidated the key interactions between compounds A5, A6, A9, and the binding pocket of SARS-CoV-2 Mpro, providing valuable insights into their mechanisms of action. These findings identify compound A9 as a promising lead for anti-SARS-CoV-2 drug development.<\/jats:p>","DOI":"10.3390\/ijms26020670","type":"journal-article","created":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T13:49:32Z","timestamp":1736862572000},"page":"670","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Optimization of SARS-CoV-2 Mpro Inhibitors by a Structure-Based Multilevel Virtual Screening Method"],"prefix":"10.3390","volume":"26","author":[{"given":"Lanlan","family":"Jing","sequence":"first","affiliation":[{"name":"Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory of 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