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oai:figshare.com:article/33719509 2026-09-14T06:15:09Z category_1 category_4 category_19 category_21 category_873 category_734 category_128 category_132 portal_63 item_type_3 month_year_09_2026

3D Electron Diffraction Elucidates the Structure of a 1,3,5-Triazin-2,4-dione Cinnamamide Covalent Inhibitor of SARS-CoV‑2 3CL^pro Meng Ge (156979) Peizhi Yan (24868678) Boxin Zhang (5820008) Bingxing Zhang (4016630) Yunfei Zhang (142098) Lei Tian (369281) Chengyuan Liang (574761) Biophysics Biochemistry Pharmacology Biotechnology Chemical Sciences not elsewhere classified Biological Sciences not elsewhere classified Hematology Infectious Diseases unsaturated michael acceptor ultralow dose conditions experimentally derived model dimensional electron diffraction anticoronavirus drug discovery work highlights 3ded 85 å resolution unsaturated cinnamamide moiety cinnamamide michael acceptor sensitive pharmaceutical nanocrystals resulting structure provides refined structural model eleven covalent 1 50 </ sub 1a </ b 0 %, yielding covalent docking analysis pro </ sup resolution analysis docking analyses 3ded ), structural analysis useful approach state organization molecular conformation like protease highest potency essential target enabled atomic crystalline state crystal structure applied three active site 45 nm The coronavirus 3-chymotrypsin-like protease (3CL^pro) is an essential target for anticoronavirus drug discovery. Eleven covalent 1,3,5-triazin-2,4-dione cinnamamides (<b>1a</b>–<b>1k</b>) bearing a Cys145-directed α,β-unsaturated Michael acceptor were synthesized and evaluated against SARS-CoV-2 3CL^pro. <b>1a</b> 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 Å resolution. The resulting structure provides an experimentally derived model of the molecular conformation and solid-state organization of compound <b>1a</b> and illustrates the geometry of the α,β-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 3CL^pro 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 3CL^pro inhibitors. 2026-09-14T00:00:00Z Dataset Dataset 10.1021/acsomega.6c03333.s001 https://figshare.com/articles/dataset/3D_Electron_Diffraction_Elucidates_the_Structure_of_a_1_3_5-Triazin-2_4-dione_Cinnamamide_Covalent_Inhibitor_of_SARS-CoV_2_3CL_sup_pro_sup_/33719509 CC BY-NC 4.0