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By using a combination of multiple computational methods including molecular docking, molecular dynamics simulations, and density functional theory calculations, the complete covalent inhibition process of ebselen is simulated for the first time. Two possible pathways with different bound conformations of ebselen are identified. The hydrolysis of the enzyme\u2010ebselen adduct is found to be the rate\u2010determining step. The simulation results show that the behavior of water molecules at the hydrolysis site is crucial to distinguish the two paths energetically. Our simulations, which are in agreement with existing experimental results, provide a theoretical basis for the rational design and mechanism exploration of ebselen\u2010based inhibitors.<\/jats:p>","DOI":"10.1002\/jcc.27181","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T07:39:30Z","timestamp":1687765170000},"page":"2086-2095","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Exploring the inhibition mechanism of <scp>SARS\u2010CoV<\/scp>\u20102 main protease by ebselen: A molecular docking, molecular dynamics simulation and <scp>DFT<\/scp> approach"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-8172-1177","authenticated-orcid":false,"given":"Wanli","family":"You","sequence":"first","affiliation":[{"name":"College of Chemistry and Materials Engineering Hunan University of Arts and Science  Changde China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuandao","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Chemistry and Materials Engineering Hunan University of Arts and Science  Changde China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,6,26]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2020.105924"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.202000223"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.1c00120"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.202000047"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.00869-22"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.02.013"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2020.127377"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2020.12.005"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2013.08.028"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31791-9"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-020-05654-1"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.29.1.12"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2223-y"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.202100582"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-23313-7"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2022.128526"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abd0345"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/app11146291"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22189792"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.21256"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.2733"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1CP00266J"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.0c00575"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/1758-2946-4-17"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/j100142a004"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.22885"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00775-009-0511-y"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1039\/D0CP05714B"},{"key":"e_1_2_7_30_1","unstructured":"M.Frisch G.Trucks H.Schlegel G.Scuseria M.Robb J.Cheeseman G.Scalmani V.Barone G.Petersson H.Nakatsuji.Wallingford CT 2016 421."},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.464913"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevB.37.785"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.3382344"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.481133"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/ar00072a001"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1021\/ar700111a"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cplett.2010.11.060"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1021\/jp810292n"},{"volume-title":"AMBER 2020","year":"2020","author":"Case D. 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