1. Academic Validation
  2. 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

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

  • J Med Chem. 2009 Aug 27;52(16):5228-40. doi: 10.1021/jm900611t.
Arun K Ghosh 1 Jun Takayama Yoann Aubin Kiira Ratia Rima Chaudhuri Yahira Baez Katrina Sleeman Melissa Coughlin Daniel B Nichols Debbie C Mulhearn Bellur S Prabhakar Susan C Baker Michael E Johnson Andrew D Mesecar
Affiliations

Affiliation

  • 1 Departments of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA. akghosh@purdue.edu
Abstract

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.

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