9puh: Difference between revisions
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==SARS-CoV-2 Papain-like Protease (PLpro) in complex with Fragment 11== | |||
<StructureSection load='9puh' size='340' side='right'caption='[[9puh]], [[Resolution|resolution]] 2.39Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[9puh]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2 Severe acute respiratory syndrome coronavirus 2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9PUH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9PUH FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.39Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1CLE:1-methylspiro[3~{H}-chromene-2,4-piperidine]-4-one'>A1CLE</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9puh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9puh OCA], [https://pdbe.org/9puh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9puh RCSB], [https://www.ebi.ac.uk/pdbsum/9puh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9puh ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
SARS-CoV-2 papain-like protease (PL(Pro)) plays a key role in viral replication and the host immune response and is a promising target for developing new antiviral treatments. We previously reported a fragment-based screen to identify hits that bind to SARS-CoV-2 PL(Pro). Here, we describe the discovery of potent PL(Pro) inhibitors by optimizing one of these hits via extensive medicinal chemistry guided by multiple X-ray structures of cocomplexes. Lead compound 46 is shown to bind to the S3 and S4 pockets with nanomolar affinity (0.4 muM) and exhibits robust cellular activity and resistance to mutation. This novel class of PL(Pro) inhibitors can potentially be used as a starting point for the development of inhibitors to combat the emergence of drug-resistant viral strains and future coronavirus outbreaks. | |||
Discovery of Fragment-Based Inhibitors of SARS-CoV-2 PL(Pro).,Wei Q, Taylor AJ, Barmade MA, Teuscher KB, Chowdhury S, Apakama C, Anderson-Daniels J, Yongqing Z, Schultz DC, Rietz TA, South TM, Crow MM, Zhao B, Amporndanai K, Sensintaffar JL, Phan J, Cherry S, Denison M, Lee T, Fesik SW J Med Chem. 2026 Jan 22;69(2):1419-1433. doi: 10.1021/acs.jmedchem.5c02832. Epub , 2026 Jan 11. PMID:41521555<ref>PMID:41521555</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Fesik | <div class="pdbe-citations 9puh" style="background-color:#fffaf0;"></div> | ||
[[Category: Taylor | == References == | ||
[[Category: Zhao | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Severe acute respiratory syndrome coronavirus 2]] | |||
[[Category: Fesik SW]] | |||
[[Category: Taylor AJ]] | |||
[[Category: Zhao B]] | |||
Revision as of 13:19, 10 February 2026
SARS-CoV-2 Papain-like Protease (PLpro) in complex with Fragment 11
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