3D Electron Diffraction Elucidates the Structure of a 1,3,5-Triazin-2,4-dione Cinnamamide Covalent Inhibitor of SARS-CoV-2 3CLpro

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Abstract 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–1k) bearing a Cys145-directed α,β-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 Å 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 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 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.

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