3ATW: Structure-based Design, Synthesis, Evaluation Of Peptide-mimetic Sars 3cl Protease Inhibitors

Citation:
Abstract
The design and evaluation of low molecular weight peptide-based severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CL) protease inhibitors are described. A substrate-based peptide aldehyde was selected as a starting compound, and optimum side-chain structures were determined, based on a comparison of inhibitory activities with Michael type inhibitors. For the efficient screening of peptide aldehydes containing a specific C-terminal residue, a new approach employing thioacetal to aldehyde conversion mediated by N-bromosuccinimide was devised. Structural optimization was carried out based on X-ray crystallographic analyses of the R188I SARS 3CL protease in a complex with each inhibitor to provide a tetrapeptide aldehyde with an IC(50) value of 98 nM. The resulting compound carried no substrate sequence, except for a P(3) site directed toward the outside of the protease. X-ray crystallography provided insights into the protein-ligand interactions.
PDB ID: 3ATWDownload
MMDB ID: 95678
PDB Deposition Date: 2011/1/20
Updated in MMDB: 2011/12
Experimental Method:
x-ray diffraction
Resolution: 2.36  Å
Source Organism:
Similar Structures:
Biological Unit for 3ATW: tetrameric; determined by author and by software (PISA)
Molecular Components in 3ATW
Label Count Molecule
Proteins (2 molecules)
2
3c-like Proteinase(Gene symbol: orf1ab)
Molecule annotation
Nucleotide(1 molecule)
2
Peptide Ace-thr-val-alc-his-h
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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