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Due to its specific attributes, this 3\u2010chymotrypsin like protease can be a reliable target for the drug design to combat COVID\u201019. Since the advent of COVID\u201019, Mpro has undergone many mutations. Here, the impact of 10 mutations based on their frequency and five more based on their proximity to the active site was investigated. For comparison purposes, the docking process was also performed against the Mpros of SARS\u2010COV and MERS\u2010COV. Four inhibitors with the highest docking score (11b, \u03b1\u2010ketoamide 13b, Nelfinavir, and PF\u201007321332) were selected for the structure\u2010based ligand design via fragment replacement, and around 2000 new compounds were thus obtained. After the screening of these new compounds, the pharmacokinetic properties of the best ones were predicted. In the last step, comparative molecular dynamics (MD) simulations, molecular mechanics Poisson\u2013Boltzmann surface area calculations (MM\/PBSA), and density functional theory calculations were performed. Among the 2000 newly designed compounds, three of them (NE1, NE2, and NE3), which were obtained by modifications of Nelfinavir, showed the highest affinity against all the Mpro targets. Together, NE1 compound is the best candidate for follow\u2010up Mpro inhibition and drug development studies.<\/jats:p>","DOI":"10.1002\/bab.2369","type":"journal-article","created":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T07:24:37Z","timestamp":1654068277000},"page":"439-457","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Exploration of potential inhibitors for SARS\u2010CoV\u20102 Mpro considering its mutants via structure\u2010based drug design, molecular docking, MD simulations, MM\/PBSA, and DFT calculations"],"prefix":"10.1002","volume":"70","author":[{"given":"Abdulrahman","family":"Ghasemlou","sequence":"first","affiliation":[{"name":"Protein Research Center Shahid Beheshti University  Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vuk","family":"Uskokovi\u0107","sequence":"additional","affiliation":[{"name":"TardigradeNano, LLC  Irvine California USA"},{"name":"Department of Mechanical Engineering San Diego State University  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0538-0252","authenticated-orcid":false,"given":"Yahya","family":"Sefidbakht","sequence":"additional","affiliation":[{"name":"Protein Research Center Shahid Beheshti University  Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,6,12]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-020-0695-z"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2016.03.003"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/v12020135"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules26030674"},{"issue":"3","key":"e_1_2_6_6_1","first-page":"1041","article-title":"Longitudinal monitoring of lactate in hospitalized and ambulatory COVID\u201019 patients","volume":"104","author":"Velavan TP","year":"2021","journal-title":"Am J Trop Med Hyg"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbab241"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/v2081803"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2020.127377"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010020\u20102286\u20109"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.25681"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12985\u2010020\u201001402\u20101"},{"key":"e_1_2_6_13_1","article-title":"Analysis of non\u2010structural proteins, NSPs of SARS\u2010CoV\u20102 as targets for computational drug designing","volume":"25","author":"Raj R","year":"2021","journal-title":"Biochem Biophys Rep"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010020\u20102223\u2010y"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.02114\u201007"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1080\/07391102.2020.1792344"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.2174\/156802606776287090"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.19424\u20100"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/minf.202000028"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2020.109721"},{"key":"e_1_2_6_21_1","first-page":"121","volume-title":"The Main Protease of SARS COV\u20102 and Its Specific Inhibitors. 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