View source for 8e6a


==Crystal structure of SARS-CoV-2 3CL protease in complex with a p-chlorophenylethanol based inhibitor==
<StructureSection load='8e6a' size='340' side='right'caption='[[8e6a]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8e6a]] is a 2 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=8E6A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8E6A 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]] 2.05&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=WIX:(1S,2S)-2-[(N-{[(2R)-2-(3-chlorophenyl)-2-hydroxypropoxy]carbonyl}-L-leucyl)amino]-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic+acid'>WIX</scene>, <scene name='pdbligand=WJ0:(1~{R},2~{S})-2-[[(2~{S})-2-[[(2~{S})-2-(3-chlorophenyl)-2-oxidanyl-propoxy]carbonylamino]-4-methyl-pentanoyl]amino]-1-oxidanyl-3-[(3~{R})-2-oxidanylidene-3,4-dihydropyrrol-3-yl]propane-1-sulfonic+acid'>WJ0</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=8e6a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8e6a OCA], [https://pdbe.org/8e6a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8e6a RCSB], [https://www.ebi.ac.uk/pdbsum/8e6a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8e6a ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The high morbidity and mortality associated with SARS-CoV-2 infection, the etiological agent of COVID-19, has had a major impact on global public health. Significant progress has been made in the development of an array of vaccines and biologics, however, the emergence of SARS-CoV-2 variants and breakthrough infections are an ongoing major concern. Furthermore, there is an existing paucity of small-molecule host and virus-directed therapeutics and prophylactics that can be used to counter the spread of SARS-CoV-2, and any emerging and re-emerging coronaviruses. We describe herein our efforts to address this urgent need by focusing on the structure-guided design of potent broad-spectrum inhibitors of SARS-CoV-2 3C-like protease (3CL(pro) or Main protease), an enzyme essential for viral replication. The inhibitors exploit the directional effects associated with the presence of a gem-dimethyl group that allow the inhibitors to optimally interact with the S4 subsite of the enzyme. Several compounds were found to potently inhibit SARS-CoV-2 and MERS-CoV 3CL proteases in biochemical and cell-based assays. Specifically, the EC50 values of aldehyde 1c and its corresponding bisulfite adduct 1d against SARS-CoV-2 were found to be 12 and 10 nM, respectively, and their CC50 values were &gt;50 muM. Furthermore, deuteration of these compounds yielded compounds 2c/2d with EC50 values 11 and 12 nM, respectively. Replacement of the aldehyde warhead with a nitrile (CN) or an alpha-ketoamide warhead or its corresponding bisulfite adduct yielded compounds 1g, 1eand1f with EC50 values 60, 50 and 70 nM, respectively. High-resolution cocrystal structures have identified the structural determinants associated with the binding of the inhibitors to the active site of the enzyme and, furthermore, have illuminated the mechanism of action of the inhibitors. Overall, the high Safety Index (SI) (SI=CC50/EC50) displayed by these compounds suggests that they are well-suited to conducting further preclinical studies.

Structure-guided design of direct-acting antivirals that exploit the gem-dimethyl effect and potently inhibit 3CL proteases of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) and middle east respiratory syndrome coronavirus (MERS-CoV).,Dampalla CS, Miller MJ, Kim Y, Zabiegala A, Nguyen HN, Madden TK, Thurman HA, Machen AJ, Cooper A, Liu L, Battaile KP, Lovell S, Chang KO, Groutas WC Eur J Med Chem. 2023 Jun 5;254:115376. doi: 10.1016/j.ejmech.2023.115376. Epub , 2023 Apr 15. PMID:37080108<ref>PMID:37080108</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8e6a" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Severe acute respiratory syndrome coronavirus 2]]
[[Category: Battaile KP]]
[[Category: Dampalla CS]]
[[Category: Groutas WC]]
[[Category: Liu L]]
[[Category: Lovell S]]