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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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Ghosh AK,Takayama J,Aubin Y,Ratia K,Chaudhuri R,Baez Y,Sleeman K,Coughlin M,Nichols DB,Mulhearn DC,Prabhakar BS,Baker SC,Johnson ME,Mesecar AD

doi

10.1021/jm900611t

subject

Has Abstract

pub_date

2009-08-27 00:00:00

pages

5228-40

issue

16

eissn

0022-2623

issn

1520-4804

journal_volume

52

pub_type

杂志文章

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