{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T05:44:42Z","timestamp":1790401482705,"version":"4.1.0"},"reference-count":62,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,4,28]],"date-time":"2020-04-28T00:00:00Z","timestamp":1588032000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["DEC-2013\/10\/E\/NZ1\/00649"],"award-info":[{"award-number":["DEC-2013\/10\/E\/NZ1\/00649"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["DEC-2015\/18\/M\/NZ1\/00427"],"award-info":[{"award-number":["DEC-2015\/18\/M\/NZ1\/00427"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The novel coronavirus whose outbreak took place in December 2019 continues to spread at a rapid rate worldwide. In the absence of an effective vaccine, inhibitor repurposing or de novo drug design may offer a longer-term strategy to combat this and future infections due to similar viruses. Here, we report on detailed classical and mixed-solvent molecular dynamics simulations of the main protease (Mpro) enriched by evolutionary and stability analysis of the protein. The results were compared with those for a highly similar severe acute respiratory syndrome (SARS) Mpro protein. In spite of a high level of sequence similarity, the active sites in both proteins showed major differences in both shape and size, indicating that repurposing SARS drugs for COVID-19 may be futile. Furthermore, analysis of the binding site\u2019s conformational changes during the simulation time indicated its flexibility and plasticity, which dashes hopes for rapid and reliable drug design. Conversely, structural stability of the protein with respect to flexible loop mutations indicated that the virus\u2019 mutability will pose a further challenge to the rational design of small-molecule inhibitors. However, few residues contribute significantly to the protein stability and thus can be considered as key anchoring residues for Mpro inhibitor design.<\/jats:p>","DOI":"10.3390\/ijms21093099","type":"journal-article","created":{"date-parts":[[2020,4,28]],"date-time":"2020-04-28T10:30:58Z","timestamp":1588069858000},"page":"3099","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":134,"title":["Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6802-8753","authenticated-orcid":false,"given":"Maria","family":"Bz\u00f3wka","sequence":"first","affiliation":[{"name":"Tunneling Group, Biotechnology Centre, ul. Krzywoustego 8, Silesian University of Technology, 44-100 Gliwice, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0183-0845","authenticated-orcid":false,"given":"Karolina","family":"Mitusi\u0144ska","sequence":"additional","affiliation":[{"name":"Tunneling Group, Biotechnology Centre, ul. Krzywoustego 8, Silesian University of Technology, 44-100 Gliwice, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agata","family":"Raczy\u0144ska","sequence":"additional","affiliation":[{"name":"Tunneling Group, Biotechnology Centre, ul. Krzywoustego 8, Silesian University of Technology, 44-100 Gliwice, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Samol","sequence":"additional","affiliation":[{"name":"Tunneling Group, Biotechnology Centre, ul. Krzywoustego 8, Silesian University of Technology, 44-100 Gliwice, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9976-0429","authenticated-orcid":false,"given":"Jack A.","family":"Tuszy\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Physics, University of Alberta, Edmont, AB T6G 2E1, Canada"},{"name":"DIMEAS, Politecnino di Torino, Corso Duca degli Abruzzi, 24, 10129 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2530-6957","authenticated-orcid":false,"given":"Artur","family":"G\u00f3ra","sequence":"additional","affiliation":[{"name":"Tunneling Group, Biotechnology Centre, ul. Krzywoustego 8, Silesian University of Technology, 44-100 Gliwice, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China","volume":"395","author":"Huang","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1056\/NEJMoa2001017","article-title":"A Novel Coronavirus from Patients with Pneumonia in China, 2019","volume":"382","author":"Zhu","year":"2020","journal-title":"N. Engl. J. 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