{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:00:07Z","timestamp":1790701207458,"version":"4.1.0"},"reference-count":34,"publisher":"American Chemical Society (ACS)","issue":"38","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F?rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["TMPFP3_210032"],"award-info":[{"award-number":["TMPFP3_210032"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82373843"],"award-info":[{"award-number":["82373843"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011710","name":"Shaanxi Provincial Science and Technology Department","doi-asserted-by":"publisher","award":["S2024-YF-ZDCXL-ZDLSF-0008"],"award-info":[{"award-number":["S2024-YF-ZDCXL-ZDLSF-0008"]}],"id":[{"id":"10.13039\/501100011710","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Research Center for the Development of Therapeutic Drugs for Serious Infectious Diseases in Shaanxi Province?s Universities and Colleges"},{"name":"Xi?an Key Laboratory for Antiviral and Antimicrobial-Resistant Bacteria Therapeutics Research","award":["2024JH-ZDSYJX-0018"],"award-info":[{"award-number":["2024JH-ZDSYJX-0018"]}]},{"name":"Xi?an International Science and Technology Cooperation Base for Anti-Infective Drug Research and Development"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The coronavirus 3-chymotrypsin-like protease (3CLpro) is an essential target for anticoronavirus drug discovery. Eleven covalent 1,3,5-triazin-2,4-dione cinnamamides (1a\u20131k) bearing a Cys145-directed \u03b1,\u03b2-unsaturated Michael acceptor were synthesized and evaluated against SARS-CoV-2 3CLpro. 1a showed the highest potency (IC50 = 92.45 nM) and was further characterized by structural and docking analyses. To determine its crystal structure, we applied three-dimensional electron diffraction (3DED), which enabled atomic-resolution analysis of nanocrystals under ultralow dose conditions. Integration of three data sets improved completeness from 58.2% to 91.0%, yielding a refined structural model at 0.85 \u00c5 resolution. The resulting structure provides an experimentally derived model of the molecular conformation and solid-state organization of compound 1a and illustrates the geometry of the \u03b1,\u03b2-unsaturated cinnamamide moiety in the crystalline state. Covalent docking analysis further suggests that the cinnamamide Michael acceptor can adopt a plausible orientation toward Cys145 within the 3CLpro active site. This work highlights 3DED as a useful approach for structural analysis of beam-sensitive pharmaceutical nanocrystals and provides experimentally derived structural information for further optimization of cinnamamide-containing 3CLpro inhibitors.<\/jats:p>","DOI":"10.1021\/acsomega.6c03333","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T07:01:38Z","timestamp":1789369298000},"page":"56849-56857","source":"Crossref","is-referenced-by-count":0,"title":["3D Electron Diffraction\nElucidates the Structure of\na 1,3,5-Triazin-2,4-dione Cinnamamide Covalent Inhibitor of SARS-CoV-2\n3CLpro"],"prefix":"10.1021","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9296-2423","authenticated-orcid":true,"given":"Meng","family":"Ge","sequence":"first","affiliation":[{"name":"Dalian University of Technology , , ,","place":["Dalian, China, 116024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3474-3224","authenticated-orcid":true,"given":"Peizhi","family":"Yan","sequence":"additional","affiliation":[{"name":"Dalian University of Technology , , ,","place":["Dalian, China, 116024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boxin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shaanxi University of Science and Technology , , ,","place":["Xi\u2019an, China, 710021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingxing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shaanxi University of Science and Technology , , ,","place":["Xi\u2019an, China, 710021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunfei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shaanxi University of Science and Technology , , ,","place":["Xi\u2019an, China, 710021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9051-9468","authenticated-orcid":true,"given":"Lei","family":"Tian","sequence":"additional","affiliation":[{"name":"Shaanxi University of Science and Technology , , ,","place":["Xi\u2019an, China, 710021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7360-8998","authenticated-orcid":true,"given":"Chengyuan","family":"Liang","sequence":"additional","affiliation":[{"name":"Shaanxi University of Science and Technology , , ,","place":["Xi\u2019an, China, 710021"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"issue":"8","key":"2026092911100609800_cit1","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1056\/NEJMoa2001017","article-title":"A Novel Coronavirus from Patients with Pneumonia\nin\nChina, 2019","volume":"382","author":"Zhu","year":"2020","journal-title":"N Engl J. 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Ethnopharmacol"},{"issue":"9","key":"2026092911100609800_cit19","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1016\/S1875-5364(24)60577-7","article-title":"Discovery and characterization of naturally occurring covalent inhibitors\nof SARS-CoV-2 Mpro from the antiviral herb Ephedra","volume":"22","author":"Hu","year":"2024","journal-title":"Chin J. Nat. Med."},{"issue":"1","key":"2026092911100609800_cit20","doi-asserted-by":"publisher","first-page":"3623","DOI":"10.1038\/s41467-021-23751-3","article-title":"Identification of pyrogallol\nas a warhead in design of covalent inhibitors\nfor the SARS-CoV-2 3CL protease","volume":"12","author":"Su","year":"2021","journal-title":"Nat. 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Biomol Chem."},{"key":"2026092911100609800_cit23","doi-asserted-by":"publisher","first-page":"118258","DOI":"10.1016\/j.bmc.2025.118258","article-title":"Synthesis\nand multitarget\ninhibitory effect of indole-based ethyl cinnamate derivatives against\nSARS-CoV-2 Mpro and cathepsins for broad-spectrum anti-coronavirus\nactivity","volume":"128","author":"Citarella","year":"2025","journal-title":"Bioorg. Med. Chem."},{"key":"2026092911100609800_cit24","doi-asserted-by":"publisher","first-page":"114046","DOI":"10.1016\/j.ejmech.2021.114046","article-title":"Design, synthesis and in vitro evaluation\nof novel SARS-CoV-2 3CLpro covalent inhibitors","volume":"229","author":"Stille","year":"2022","journal-title":"Eur. J. Med. 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Sci."},{"key":"2026092911100609800_cit28","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1039\/D0FD00015A","article-title":"Can 3D electron\ndiffraction provide accurate atomic structures of metal-organic frameworks?","volume":"225","author":"Huang","year":"2021","journal-title":"Faraday Discuss."},{"issue":"16","key":"2026092911100609800_cit29","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202317695","article-title":"Phase Identification and Discovery of an Elusive Polymorph\nof Drug-Polymer Inclusion Complex Using Automated 3D Electron Diffraction","volume":"63","author":"Lightowler","year":"2024","journal-title":"Angew. Chem., Int. Ed. Engl."},{"issue":"20","key":"2026092911100609800_cit30","doi-asserted-by":"publisher","first-page":"21330","DOI":"10.1021\/acs.jmedchem.5c01199","article-title":"Discovery\nof Highly Potent Noncovalent Inhibitors of\nSARS-CoV-2 Main Protease through Computer-Aided Drug Design","volume":"68","author":"Okabe","year":"2025","journal-title":"J. Med. Chem."},{"key":"2026092911100609800_cit31","unstructured":"Liang, C.; Xin, L.; Tian, L.; Li, J.; Xie, X.; Zhang, D.; Wu, K.; Zhang, S.; Yang, X.; Liu, S.; et al.; 3-Triazolyl Methyl-1,3,5-triazine-2,4-dione\nCompounds and Preparation Method and Application Thereof. U.S. Patent US 11,612,603 B1, 2023."},{"issue":"3","key":"2026092911100609800_cit32","doi-asserted-by":"publisher","first-page":"263","DOI":"10.3390\/cryst11030263","article-title":"Three-Dimensional Electron Diffraction for Structural\nAnalysis of Beam-Sensitive Metal-Organic Frameworks","volume":"11","author":"Ge","year":"2021","journal-title":"Crystals"},{"issue":"6","key":"2026092911100609800_cit33","doi-asserted-by":"publisher","first-page":"1652","DOI":"10.1107\/S1600576718015145","article-title":"High-throughput\ncontinuous rotation electron diffraction data acquisition via software\nautomation","volume":"51","author":"Cichocka","year":"2018","journal-title":"J. Appl. Crystallogr."},{"issue":"3","key":"2026092911100609800_cit34","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1107\/S1600576717005854","article-title":"Serial electron crystallography: merging diffraction data through\nrank aggregation","volume":"50","author":"Smeets","year":"2017","journal-title":"J. Appl. Crystallogr."}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.6c03333","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/38\/56849\/68496385\/acsomega.6c03333.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/38\/56849\/68496385\/acsomega.6c03333.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:09:38Z","timestamp":1790698178000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/11\/38\/56849\/5429183\/3D-Electron-Diffraction-Elucidates-the-Structure"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,14]]},"references-count":34,"journal-issue":{"issue":"38","published-online":{"date-parts":[[2026,9,14]]},"published-print":{"date-parts":[[2026,9,29]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.6c03333","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,14]]}}}