147959-15-7Relevant articles and documents
Severe acute respiratory syndrome coronavirus papain-like novel protease inhibitors: Design, synthesis, protein-ligand X-ray structure and biological evaluation
Ghosh, Arun K.,Takayama, Jun,Rao, Kalapala Venkateswara,Ratia, Kiira,Chaudhuri, Rima,Mulhearn, Debbie C.,Lee, Hyun,Nichols, Daniel B.,Baliji, Surendranath,Baker, Susan C.,Johnson, Michael E.,Mesecar, Andrew D.
experimental part, p. 4968 - 4979 (2010/09/05)
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.
