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It possesses allosteric sites that can hinder its catalytic activity, with some of these sites located at or near the dimerization interface. Among them, sites #2 and #5 possess druggable pockets and are predicted to bind drug\u2010like molecules. Consequently, a commercially available ligand library containing ~7 million ligands was used to target site #2 via structure\u2010based virtual screening. After extensive filtering, docking, and post\u2010docking analyses, 53 compounds were chosen for biological testing. An oxindole derivative was identified as a M<jats:sup>pro<\/jats:sup> non\u2010competitive reversible inhibitor with a K<jats:sub>i<\/jats:sub> of 115\u2005\u03bcM and an IC<jats:sub>50<\/jats:sub> of 101.9\u2005\u03bcM. Throughout the 200\u2005ns\u2010long MD trajectories, our top hit has shown a very stable binding mode, forming several interactions with residues in sites #2 and #5. Moreover, derivatives of our top hit were acquired for biological testing to gain deeper insights into their structure\u2010activity relationship. To sum up, drug\u2010like allosteric inhibitors seem promising and can provide us with an additional weapon in our war against the recent pandemic, and possibly other coronaviruses\u2010caused diseases.<\/jats:p>","DOI":"10.1002\/cbdv.202301176","type":"journal-article","created":{"date-parts":[[2023,10,20]],"date-time":"2023-10-20T11:09:28Z","timestamp":1697800168000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The Discovery of Novel Small Oxindole\u2010Based Inhibitors Targeting the SARS\u2010CoV\u20102 Main Protease (M<sup>pro<\/sup>)"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9307-3644","authenticated-orcid":false,"given":"Lara","family":"Alzyoud","sequence":"first","affiliation":[{"name":"College of Pharmacy Al Ain University  Abu Dhabi 64141 United Arab Emirates"},{"name":"AAU Health and Biomedical Research Center Al Ain University  Abu Dhabi 64141 United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radwa E.","family":"Mahgoub","sequence":"additional","affiliation":[{"name":"College of Pharmacy Al Ain University  Abu Dhabi 64141 United Arab Emirates"},{"name":"AAU Health and Biomedical Research Center Al Ain University  Abu Dhabi 64141 United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feda E.","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomics College of Medicine and Health Sciences United Arab Emirates University  Al-Ain 15551 United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bassam R.","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomics College of Medicine and Health Sciences United Arab Emirates University  Al-Ain 15551 United Arab Emirates"},{"name":"Zayed Centre for Health Sciences United Arab Emirates University  Al-Ain 15551 United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Science Division New York University Abu Dhabi  Abu Dhabi 129188 United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wael M.","family":"Rabeh","sequence":"additional","affiliation":[{"name":"Science Division New York University Abu Dhabi  Abu Dhabi 129188 United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noor","family":"Atatreh","sequence":"additional","affiliation":[{"name":"College of Pharmacy Al Ain University  Abu Dhabi 64141 United Arab Emirates"},{"name":"AAU Health and Biomedical Research Center Al Ain University  Abu Dhabi 64141 United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2240-8037","authenticated-orcid":false,"given":"Mohammad A.","family":"Ghattas","sequence":"additional","affiliation":[{"name":"College of Pharmacy Al Ain University  Abu Dhabi 64141 United Arab Emirates"},{"name":"AAU Health and Biomedical Research Center Al Ain University  Abu Dhabi 64141 United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,11,9]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa030781"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01244-13"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2001017"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2020.11.024"},{"key":"e_1_2_10_5_1","volume":"12","author":"Pal M.","year":"2020","journal-title":"Cureus"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2020.114225"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9051267"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12250-015-3711-3"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb3405"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fchem.2021.622898"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.2174\/138161206779010369"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1107\/S2052252520012634"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2021.167118"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109892"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-88630-9"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf7945"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2021.105075"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2008.01.023"},{"key":"e_1_2_10_19_1","first-page":"2535","volume":"10","author":"Wang Y. 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