title: 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.
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.
authors: Departments of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA. akghosh@purdue.edu
authors: Arun K
authors: AK
authors: Ghosh
authors: Jun
authors: J
authors: Takayama
authors: Yoann
authors: Y
authors: Aubin
authors: Kiira
authors: K
authors: Ratia
authors: Rima
authors: R
authors: Chaudhuri
authors: Yahira
authors: Y
authors: Baez
authors: Katrina
authors: K
authors: Sleeman
authors: Melissa
authors: M
authors: Coughlin
authors: Daniel B
authors: DB
authors: Nichols
authors: Debbie C
authors: DC
authors: Mulhearn
authors: Bellur S
authors: BS
authors: Prabhakar
authors: Susan C
authors: SC
authors: Baker
authors: Michael E
authors: ME
authors: Johnson
authors: Andrew D
authors: AD
authors: Mesecar
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002522:Chlorocebus aethiops; D000086782:Coronavirus 3C Proteases; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases; D015195:Drug Design; D008958:Models, Molecular; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects* / Q000201:enzymology; D014709:Vero Cells; D014764:Viral Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000998:Antiviral Agents; D001549:Benzamides; C550443:N-methyl-5-methylamino-2-methyl-N-((R)-1-(1-naphthyl)ethy)benzamide; D009281:Naphthalenes; D011480:Protease Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases