{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:36:04Z","timestamp":1790613364819,"version":"4.1.0"},"reference-count":48,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T00:00:00Z","timestamp":1739491200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T00:00:00Z","timestamp":1739491200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chemistry &amp;amp; Biodiversity"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    As severe acute respiratory syndrome coronavirus 2 (SARS\u2011CoV\u20112) variants continue to emerge, there is an urgent need to develop more effective antiviral drugs capable of combating the COVID\u201019 pandemic. The main protease (M\n                    <jats:sup>pro<\/jats:sup>\n                    ) of SARS\u2010CoV\u20102 is an evolutionarily conserved drug discovery target. The present study mainly focused on chemoinformatics computational methods to investigate the efficacy of our newly designed trifluoromethyl\u20101,3,4\u2010oxadiazole amide derivatives as SARS\u2010CoV\u20102 M\n                    <jats:sup>pro<\/jats:sup>\n                    inhibitors. Drug\u2010likeness absorption, distribution, metabolism, excretion, and toxicity analysis, molecular docking simulation, density functional theory (DFT), and molecular dynamics simulation methods were included. A comprehensive drug\u2010likeness analysis was performed on the 14 newly designed compounds (\n                    <jats:bold>1a<\/jats:bold>\n                    \u2013\n                    <jats:bold>1n<\/jats:bold>\n                    ), and this series of small molecule inhibitors showed potential anti\u2010SARS\u2010CoV\u20102 activity. In order to reveal the mechanism of drug interaction, these novel compounds were classified by structure, and molecular docking simulations were performed. The results showed good interactions and identified the key amino acid residue GLY\u2010143. Further DFT analysis using B3LYP\u2010D3BJ functional and 6\u2010311 + + G (d, p) basis set was performed to optimize the optimal configuration of the M\n                    <jats:sup>pro<\/jats:sup>\n                    inhibitors, and the infrared spectrum of the vibration frequency was analyzed to clearly understand the structure and stability of the drug. The electrostatic potential map was analyzed to predict the reactivity of functional groups and protein\u2010substrate interactions. The frontier molecular orbital analysis and density of states map showed the reactivity level and stability of the drug itself, among which\n                    <jats:bold>1i<\/jats:bold>\n                    had the smallest energy gap difference (\u0394\n                    <jats:sub>Egap<\/jats:sub>\n                    = 3.64 ev), showing good reactivity. The analysis of global reactivity descriptors such as electrophilic index (\u03c9) and chemical potential (\u03bc) also showed that our newly designed M\n                    <jats:sup>pro<\/jats:sup>\n                    inhibitors had stronger interactions. Molecular dynamics simulation further revealed the stable binding of the M\n                    <jats:sup>pro<\/jats:sup>\n                    inhibitors in a solvent environment. The binding free energy results calculated by Molecular Mechanics \/ Poisson Boltzmann Surface Area (MM\/PBSA) all exceeded the Food and Drug Administration\u2010approved standard reference drug (Nirmatrelvir), and the free energy landscape and principal component analysis also further described the energy sites formed during the binding process between the drug molecule and the ligand\u2010protein and the changes in conformation. These new series of small molecule inhibitors studied in this work will provide the necessary theoretical basis for the synthesis and activity evaluation of novel SARS\u2010CoV\u20102 M\n                    <jats:sup>pro<\/jats:sup>\n                    inhibitors.\n                  <\/jats:p>","DOI":"10.1002\/cbdv.202403179","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T03:54:56Z","timestamp":1737690896000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Discovery of Severe Acute Respiratory Syndrome Coronavirus 2 Main Protease Inhibitors through Rational Design of Novel Fluorinated 1,3,4\u2010oxadiazole Amide Derivatives: An In\u2010Silico Study"],"prefix":"10.1002","volume":"22","author":[{"given":"Huiying","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Shanghai for Science and Technology Shanghai P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heping","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Shanghai for Science and Technology Shanghai P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhonghua","family":"Wang","sequence":"additional","affiliation":[{"name":"Shanghai Engineering Research Center of Green Fluoropharmaceutical Technology, School of Chemical and Environmental Engineering Shanghai Institute of Technology Shanghai P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1140-994X","authenticated-orcid":false,"given":"Fei","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Shanghai for Science and Technology Shanghai P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,14]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"WHO Coronavirus (COVID\u201019) Dashboard https:\/\/covid19.who.int(Accessed 1 October 2024)."},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.m1985"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-02156-9"},{"key":"e_1_2_9_5_1","doi-asserted-by":"crossref","first-page":"384","DOI":"10.33588\/rn.7211.2021230","article-title":"S\u00edndrome Post\u2010COVID\u201019: Epidemiolog\u00eda, Criterios Diagn\u00f3sticos y Mecanismos Patog\u00e9nicos Implicados","volume":"72","author":"Carod\u2010Artal F.","year":"2021","journal-title":"Revista de Neurolog\u00eda"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.12.032"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.06.020"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S283686"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-micro-110520-023212"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/d41573-020-00016-0"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2020.112559"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.151"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c01005"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb3405"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b01828"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b01461"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27082523"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abm7621"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abg5827"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl4784"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf1611"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.o1397"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00665"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom11040607"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2223-y"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom13091339"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2018.11.032"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201000066"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1080\/14756366.2022.2078969"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2023.115721"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.0c00898"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b00258"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1MD00230A"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00706-018-2303-y"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm040204g"},{"key":"e_1_2_9_36_1","doi-asserted-by":"crossref","unstructured":"F.Xiong Y.Zhang J.Jiao Y.Zhu T.Mo andY.Li \u201cTowards New Bioactive Fluorine\u2010Containing 1 3 4\u2010oxadiazole\u2010amide Derivatives: Synthesis Antibacterial Activity Molecular Docking and Molecular Dynamics Simulation Study \u201dMolecular Diversity ahead of print June 24 2024 10.1007\/s11030\u2010024\u201010893\u2010x.","DOI":"10.21203\/rs.3.rs-4148372\/v1"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab255"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2NJ04492G"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.4993215"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.2436888"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.22885"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/0263-7855(96)00018-5"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.3390\/computation10020014"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1021\/jp990092i"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.27235"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsusc.2021.151780"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1NJ02542B"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2012.09.019"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diamond.2022.109142"}],"container-title":["Chemistry &amp; 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