Structure-based design, synthesis, and biological evaluation of a series of novel and reversible inhibitors for the severe acute respiratory syndrome-coronavirus papain-like protease.

Ghosh, Arun K; Takayama, Jun; Aubin, Yoann; Ratia, Kiira; Chaudhuri, Rima; Baez, Yahira; Sleeman, Katrina; Coughlin, Melissa; Nichols, Daniel B; Mulhearn, Debbie C; Prabhakar, Bellur S; Baker, Susan C; Johnson, Michael E; Mesecar, Andrew D

We describe here the design, synthesis, molecular modeling, and biological evaluation of a series of small molecule, nonpeptide inhibitors of SARS-CoV PLpro. Our initial lead compound was identified via high-throughput screening of a diverse chemical library. We subsequently carried out structure-activity relationship studies and optimized the lead structure to potent inhibitors that have shown antiviral activity against SARS-CoV infected Vero E6 cells. Upon the basis of the X-ray crystal structure of inhibitor 24-bound to SARS-CoV PLpro, a drug design template was created. Our structure-based modification led to the design of a more potent inhibitor, 2 (enzyme IC(50) = 0.46 microM; antiviral EC(50) = 6 microM). Interestingly, its methylamine derivative, 49, displayed good enzyme inhibitory potency (IC(50) = 1.3 microM) and the most potent SARS antiviral activity (EC(50) = 5.2 microM) in the series. We have carried out computational docking studies and generated a predictive 3D-QSAR model for SARS-CoV PLpro inhibitors.