📄 Severe acute respiratory syndrome coronavirus papain-like novel protease inhibitors: Design, synthesis, protein-ligand X-ray structure and biological evaluation

The design, synthesis, X-ray crystal structure, molecular modeling, and biological evaluation of a series of new generation SARS-CoV PLpro inhibitors are described. A new lead compound 3 (6577871) was identified via high-throughput screening of a diverse chemical library. Subsequently, we carried out lead optimization and structure-activity studies to provide a series of improved inhibitors that show potent PLpro inhibition and antiviral activity against SARS-CoV infected Vero E6 cells. Interestingly, the (S)-Me inhibitor 15h (enzyme IC50 = 0.56 mn; antiviral EC50 = 9.1 mn;) and the corresponding (R)-Me 15g (IC50 = 0.32 mn; antiviral EC 50 = 9.1 mn;) are the most potent compounds in this series, with nearly equivalent enzymatic inhibition and antiviral activity. A protein-ligand X-ray structure of 15g-bound SARS-CoV PLpro and a corresponding model of 15h docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions. © 2010 American Chemical Society.

keywords 🔗 crystal structure (114)

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