3mj5

Publication Abstract from PubMed

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 IC(50) = 0.56 muM; antiviral EC(50) = 9.1 muM) and the corresponding (R)-Me 15g (IC(50) = 0.32 muM; antiviral EC(50) = 9.1 muM) 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.

Severe Acute Respiratory Syndrome Coronavirus Papain-like Novel Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation.,Ghosh AK, Takayama J, Rao KV, Ratia K, Chaudhuri R, Mulhearn DC, Lee H, Nichols DB, Baliji S, Baker SC, Johnson ME, Mesecar AD J Med Chem. 2010 Jun 9. PMID:20527968^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.