{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:33:40Z","timestamp":1788910420759,"version":"build-2803163510"},"reference-count":51,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2021,12,5]],"date-time":"2021-12-05T00:00:00Z","timestamp":1638662400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>SARS-CoV-2 is highly homologous to SARS-CoV. To date, the main protease (Mpro) of SARS-CoV-2 is regarded as an important drug target for the treatment of Coronavirus Disease 2019 (COVID-19). Some experiments confirmed that several HIV protease inhibitors present the inhibitory effects on the replication of SARS-CoV-2 by inhibiting Mpro. However, the mechanism of action has still not been studied very clearly. In this work, the interaction mechanism of four HIV protease inhibitors Darunavir (DRV), Lopinavir (LPV), Nelfinavir (NFV), and Ritonavire (RTV) targeting SARS-CoV-2 Mpro was explored by applying docking, molecular dynamics (MD) simulations, and MM\u2013GBSA methods using the broad-spectrum antiviral drug Ribavirin (RBV) as the negative and nonspecific control. Our results revealed that LPV, RTV, and NFV have higher binding affinities with Mpro, and they all interact with catalytic residues His41 and the other two key amino acids Met49 and Met165. Pharmacophore model analysis further revealed that the aromatic ring, hydrogen bond donor, and hydrophobic group are the essential infrastructure of Mpro inhibitors. Overall, this study applied computational simulation methods to study the interaction mechanism of HIV-1 protease inhibitors with SARS-CoV-2 Mpro, and the findings provide useful insights for the development of novel anti-SARS-CoV-2 agents for the treatment of COVID-19.<\/jats:p>","DOI":"10.3390\/molecules26237385","type":"journal-article","created":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T03:10:38Z","timestamp":1638760238000},"page":"7385","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Computational Simulation of HIV Protease Inhibitors to the Main Protease (Mpro) of SARS-CoV-2: Implications for COVID-19 Drugs Design"],"prefix":"10.3390","volume":"26","author":[{"given":"Wei","family":"Yu","sequence":"first","affiliation":[{"name":"Institute of Biomedicine, Jinan University, Guangzhou 510632, China"},{"name":"MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi\u2019an Jiaotong University, Xi\u2019an 710049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomin","family":"Wu","sequence":"additional","affiliation":[{"name":"Anhui Province Key Laboratory of Pollutant Sensitive Materials and Environmental Remediation, College of Life Sciences, Huaibei Normal University, Huaibei 235000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizhen","family":"Zhao","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi\u2019an Jiaotong University, Xi\u2019an 710049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, Jinan University, Guangzhou 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6969-8177","authenticated-orcid":false,"given":"Zhiwei","family":"Yang","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi\u2019an Jiaotong University, Xi\u2019an 710049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0793-9339","authenticated-orcid":false,"given":"Xiaochun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Anhui Province Key Laboratory of Pollutant Sensitive Materials and Environmental Remediation, College of Life Sciences, Huaibei Normal University, Huaibei 235000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Ren","sequence":"additional","affiliation":[{"name":"Zhuhai College of Science and Technology, Zhuhai 519041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueming","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, Jinan University, Guangzhou 510632, China"},{"name":"Zhuhai Trinomab Biotechnology Co., Ltd., Zhuhai 519040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changwen","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, Jinan University, Guangzhou 510632, China"},{"name":"Zhuhai Trinomab Biotechnology Co., Ltd., Zhuhai 519040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengming","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, Jinan University, Guangzhou 510632, China"},{"name":"Zhuhai Trinomab Biotechnology Co., Ltd., Zhuhai 519040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongfeng","family":"Chen","sequence":"additional","affiliation":[{"name":"Zhuhai Trinomab 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