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4OW0

X-Ray Structural and Biological Evaluation of a Series of Potent and Highly Selective Inhibitors of Human Coronavirus Papain-Like Proteases

Summary for 4OW0
Entry DOI10.2210/pdb4ow0/pdb
Related4OVZ
Descriptorpapain-like protease, ZINC ION, N-[(3-fluorophenyl)methyl]-1-[(1R)-1-naphthalen-1-ylethyl]piperidine-4-carboxamide, ... (6 entities in total)
Functional Keywordscov, coronavirus, hcov, human coronavirus, sars, severe acute respiratory syndrome, mers, middle east respiratory syndrome, plpro, papain-like protease; inhibitor, complex, dub, deubiquitinating enzyme, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
Biological sourceSARS coronavirus
Cellular locationNon-structural protein 3: Host membrane ; Multi-pass membrane protein . Non-structural protein 4: Host membrane ; Multi-pass membrane protein . Non-structural protein 6: Host membrane ; Multi-pass membrane protein . Non-structural protein 7: Host cytoplasm, host perinuclear region . Non-structural protein 8: Host cytoplasm, host perinuclear region . Non-structural protein 9: Host cytoplasm, host perinuclear region . Non-structural protein 10: Host cytoplasm, host perinuclear region : P0C6U8
Total number of polymer chains2
Total formula weight72374.84
Authors
Baez-Santos, Y.M.,Mesecar, A. (deposition date: 2014-01-28, release date: 2014-04-23, Last modification date: 2023-11-15)
Primary citationBaez-Santos, Y.M.,Barraza, S.J.,Wilson, M.W.,Agius, M.P.,Mielech, A.M.,Davis, N.M.,Baker, S.C.,Larsen, S.D.,Mesecar, A.D.
X-ray Structural and Biological Evaluation of a Series of Potent and Highly Selective Inhibitors of Human Coronavirus Papain-like Proteases.
J.Med.Chem., 57:2393-2412, 2014
Cited by
PubMed Abstract: Structure-guided design was used to generate a series of noncovalent inhibitors with nanomolar potency against the papain-like protease (PLpro) from the SARS coronavirus (CoV). A number of inhibitors exhibit antiviral activity against SARS-CoV infected Vero E6 cells and broadened specificity toward the homologous PLP2 enzyme from the human coronavirus NL63. Selectivity and cytotoxicity studies established a more than 100-fold preference for the coronaviral enzyme over homologous human deubiquitinating enzymes (DUBs), and no significant cytotoxicity in Vero E6 and HEK293 cell lines is observed. X-ray structural analyses of inhibitor-bound crystal structures revealed subtle differences between binding modes of the initial benzodioxolane lead (15g) and the most potent analogues 3k and 3j, featuring a monofluoro substitution at para and meta positions of the benzyl ring, respectively. Finally, the less lipophilic bis(amide) 3e and methoxypyridine 5c exhibit significantly improved metabolic stability and are viable candidates for advancing to in vivo studies.
PubMed: 24568342
DOI: 10.1021/jm401712t
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.1 Å)
Structure validation

239149

數據於2025-07-23公開中

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