View source for 7tiw


==Crystal structure of SARS-CoV-2 3CL in complex with inhibitor EB54==
<StructureSection load='7tiw' size='340' side='right'caption='[[7tiw]], [[Resolution|resolution]] 1.68&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7TIW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TIW 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]] 1.68&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=I54:(1S,2S)-2-[(N-{[(2-chlorophenyl)methoxy]carbonyl}-L-leucyl)amino]-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic+acid'>I54</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=7tiw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tiw OCA], [https://pdbe.org/7tiw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tiw RCSB], [https://www.ebi.ac.uk/pdbsum/7tiw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tiw ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The SARS-CoV-2 3CL protease is a critical drug target for small molecule COVID-19 therapy, given its likely druggability and essentiality in the viral maturation and replication cycle. Based on the conservation of 3CL protease substrate binding pockets across coronaviruses and using screening, we identified four structurally distinct lead compounds that inhibit SARS-CoV-2 3CL protease. After evaluation of their binding specificity, cellular antiviral potency, metabolic stability, and water solubility, we prioritized the GC376 scaffold as being optimal for optimization. We identified multiple drug-like compounds with &lt;10 nM potency for inhibiting SARS-CoV-2 3CL and the ability to block SARS-CoV-2 replication in human cells, obtained co-crystal structures of the 3CL protease in complex with these compounds, and determined that they have pan-coronavirus activity. We selected one compound, termed coronastat, as an optimized lead and characterized it in pharmacokinetic and safety studies in vivo. Coronastat represents a new candidate for a small molecule protease inhibitor for the treatment of SARS-CoV-2 infection for eliminating pandemics involving coronaviruses.

Development of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19.,Liu H, Iketani S, Zask A, Khanizeman N, Bednarova E, Forouhar F, Fowler B, Hong SJ, Mohri H, Nair MS, Huang Y, Tay NES, Lee S, Karan C, Resnick SJ, Quinn C, Li W, Shion H, Xia X, Daniels JD, Bartolo-Cruz M, Farina M, Rajbhandari P, Jurtschenko C, Lauber MA, McDonald T, Stokes ME, Hurst BL, Rovis T, Chavez A, Ho DD, Stockwell BR Nat Commun. 2022 Apr 7;13(1):1891. doi: 10.1038/s41467-022-29413-2. PMID:35393402<ref>PMID:35393402</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7tiw" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Bednarova E]]
[[Category: Chavez A]]
[[Category: Forouhar F]]
[[Category: Fowler B]]
[[Category: Ho DD]]
[[Category: Hong SJ]]
[[Category: Huang Y]]
[[Category: Hurst B]]
[[Category: Iketani S]]
[[Category: Jurtschenko C]]
[[Category: Karan C]]
[[Category: Khanizeman N]]
[[Category: Lauber MA]]
[[Category: Lee S]]
[[Category: Li W]]
[[Category: Liu H]]
[[Category: McDonald T]]
[[Category: Mohri H]]
[[Category: Nair MS]]
[[Category: Quinn C]]
[[Category: Resnick SJ]]
[[Category: Rovis T]]
[[Category: Shion H]]
[[Category: Stockwell BR]]
[[Category: Stokes ME]]
[[Category: Tay NES]]
[[Category: Zack A]]