From Genome to Drug Lead: Identification of a Small‐Molecule Inhibitor (I) of the SARS Virus.

Dooley, Andrea J.; Shindo, Nice; Taggart, Barbara; Park, Jewn‐Giew; Pang, Yuan Ping

doi:10.1002/chin.200616112

Cited by 2 publications

(2 citation statements)

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“…These warhead groups include Michael acceptors, 23,29,34 aldehydes, 29,37 epoxy ketones, 32 halo methyl ketones, 33 and a few others. These inhibitors have been discovered using various techniques such as structure based virtual screening, 24,36,39,35 pharmacophore based screening 40 as well as high through screening 41 methodologies. This is followed by a nucleophilic attack by the catalytic cys-teine and covalent adduct formation.…”

Section: Introductionmentioning

confidence: 99%

Structure-based virtual screening against SARS-3CLpro to identify novel non-peptidic hits

Mukherjee

Desai

Ross

et al. 2008

Bioorganic & Medicinal Chemistry

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Severe acute respiratory syndrome is a highly infectious upper respiratory tract disease caused by SARS-CoV, a previously unidentified human coronavirus. SARS-3CL(pro) is a viral cysteine protease critical to the pathogen's life cycle and hence a therapeutic target of importance. The recently elucidated crystal structures of this enzyme provide an opportunity for the discovery of inhibitors through rational drug design. In the current study, Gold docking program was utilized to conduct extensive docking studies against the target crystal structure to develop a robust and predictive docking protocol. The validated docking protocol was used to conduct a structure-based virtual screening of the Asinex Platinum collection. Biological evaluation of a screened selection of compounds was carried out to identify novel inhibitors of the viral protease.

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Section: Introductionmentioning

confidence: 99%

Structure-based virtual screening against SARS-3CLpro to identify novel non-peptidic hits

Mukherjee

Desai

Ross

et al. 2008

Bioorganic & Medicinal Chemistry

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“…Various experimental techniques and modeling methods, such as structure-based discovery, [16][17][18][19][20] experimental screening, [21][22][23][24][25] and virtual screening, [26][27][28][29][30][31][32][33] have been employed in the search for effective anti-SARS inhibitors. Although the efficacies of some compounds were verified and characterized by biochemical and/or cell culture-based assays, the inhibition mechanism remains unclear for some of them primarily due to the lack of structural information.…”

Section: Introductionmentioning

confidence: 99%

Molecular docking identifies the binding of 3-chloropyridine moieties specifically to the S1 pocket of SARS-CoV Mpro

Niu

Jiang

Zhang

et al. 2008

Bioorganic & Medicinal Chemistry

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The 3C-like main proteinase of the severe acute respiratory syndrome (SARS) coronavirus, SARS-CoV M(pro), is widely considered to be a major drug target for the development of anti-SARS treatment. Based on the chemical structure of a lead compound from a previous screening, we have designed and synthesized a number of non-peptidyl inhibitors, some of which have shown significantly improved inhibitory activity against SARS-CoV M(pro) with IC(50) values of approximately 60 nM. In the absence of SARS-CoV M(pro) crystal structures in complex with these synthetic inhibitors, molecular docking tools have been employed to study possible interactions between these inhibitors and SARS-CoV M(pro). The docking results suggest two major modes for the initial binding of these inhibitors to the active site of SARS-CoV M(pro). They also establish a structural basis for the 'core design' of these inhibitors by showing that the 3-chloropyridine functions common to all of the present inhibitors tend to cluster in the S1 specificity pocket. In addition, intrinsic flexibility in the S4 pocket allows for the accommodation of bulky groups such as benzene rings, suggesting that this structural plasticity can be further exploited for optimizing inhibitor-enzyme interactions that should promote a tighter binding mode. Most importantly, our results provide the structural basis for rational design of wide-spectrum antiviral drugs targeting the chymotrypsin-like cysteine proteinases from coronaviruses and picornaviruses.

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From Genome to Drug Lead: Identification of a Small‐Molecule Inhibitor (I) of the SARS Virus.

Abstract: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Cited by 2 publications

References 1 publication

Structure-based virtual screening against SARS-3CLpro to identify novel non-peptidic hits

Structure-based virtual screening against SARS-3CLpro to identify novel non-peptidic hits

Molecular docking identifies the binding of 3-chloropyridine moieties specifically to the S1 pocket of SARS-CoV Mpro

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