View source for 8rjz


==Crystal structure of SARS-CoV-2 main protease (MPro) in complex with the non-covalent inhibitor GUE-3801 (compound 80 in publication)==
<StructureSection load='8rjz' size='340' side='right'caption='[[8rjz]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8rjz]] 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=8RJZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8RJZ 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]] 1.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1H1I:(7~{S})-6-[2-[2,4-bis(chloranyl)phenoxy]ethanoyl]-14-fluoranyl-10-(iminomethyl)-9-methyl-7-(phenylmethyl)-2-oxa-6,9,10-triazabicyclo[10.4.0]hexadeca-1(12),13,15-trien-8-one'>A1H1I</scene>, <scene name='pdbligand=B3P:2-[3-(2-HYDROXY-1,1-DIHYDROXYMETHYL-ETHYLAMINO)-PROPYLAMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>B3P</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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=8rjz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8rjz OCA], [https://pdbe.org/8rjz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8rjz RCSB], [https://www.ebi.ac.uk/pdbsum/8rjz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8rjz ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/A0A8B1K053_SARS2 A0A8B1K053_SARS2] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Given the crucial role of the main protease (M(pro)) in the replication cycle of SARS-CoV-2, this viral cysteine protease constitutes a high-profile drug target. We investigated peptidomimetic azapeptide nitriles as auspicious, irreversibly acting inhibitors of M(pro). Our systematic approach combined an M(pro) active-site scanning by combinatorially assembled azanitriles with structure-based design. Encouraged by the bioactive conformation of open-chain inhibitors, we conceptualized the novel chemotype of macrocyclic azanitriles whose binding mode was elucidated by cocrystallization. This strategy provided a favorable entropic contribution to target binding and resulted in the development of the extraordinarily potent M(pro) inhibitor 84 with an IC(50) value of 3.23 nM and a second-order rate constant of inactivation, k(inac)/K(i), of 448,000 M(-1)s(-1). The open-chain M(pro) inhibitor 58, along with the macrocyclic compounds 83 and 84, a broad-spectrum anticoronaviral agent, demonstrated the highest antiviral activity with EC(50) values in the single-digit micromolar range. Our findings are expected to promote the future development of peptidomimetic M(pro) inhibitors as anti-SARS-CoV-2 agents.

Macrocyclic Azapeptide Nitriles: Structure-Based Discovery of Potent SARS-CoV-2 Main Protease Inhibitors as Antiviral Drugs.,Breidenbach J, Voget R, Si Y, Hingst A, Claff T, Sylvester K, Wolf V, Krasniqi V, Useini A, Strater N, Ogura Y, Kawaguchi A, Muller CE, Gutschow M J Med Chem. 2024 May 16. doi: 10.1021/acs.jmedchem.4c00053. PMID:38753594<ref>PMID:38753594</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8rjz" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Severe acute respiratory syndrome coronavirus 2]]
[[Category: Claff T]]
[[Category: Guetschow M]]
[[Category: Mueller CE]]
[[Category: Strater N]]
[[Category: Sylvester K]]
[[Category: Useini A]]