View source for 8stz


==Structure of the SARS-CoV-2 main protease in complex with inhibitor MPI37==
<StructureSection load='8stz' size='340' side='right'caption='[[8stz]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8stz]] is a 1 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=8STZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8STZ 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]] 1.85&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=WGI:(phenylmethyl)+(3~{S})-3-[[(2~{S})-1-oxidanyl-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]carbamoyl]-2-azaspiro[4.5]decane-2-carboxylate'>WGI</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=8stz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8stz OCA], [https://pdbe.org/8stz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8stz RCSB], [https://www.ebi.ac.uk/pdbsum/8stz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8stz ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
SARS-CoV-2, the COVID-19 pathogen, relies on its main protease (M(Pro)) for replication and pathogenesis. M(Pro) is a demonstrated target for the development of antivirals for SARS-CoV-2. Past studies have systematically explored tripeptidyl inhibitors such as nirmatrelvir as M(Pro) inhibitors. However, dipeptidyl inhibitors especially those with a spiro residue at their P2 position have not been systematically investigated. In this work, we synthesized about 30 dipeptidyl M(Pro) inhibitors and characterized them on enzymatic inhibition potency, structures of their complexes with M(Pro), cellular M(Pro) inhibition potency, antiviral potency, cytotoxicity, and in vitro metabolic stability. Our results indicated that M(Pro) has a flexible S2 pocket to accommodate inhibitors with a large P2 residue and revealed that dipeptidyl inhibitors with a large P2 spiro residue such as (S)-2-azaspiro [4,4]nonane-3-carboxylate and (S)-2-azaspiro[4,5]decane-3-carboxylate have favorable characteristics. One compound, MPI60, containing a P2 (S)-2-azaspiro[4,4]nonane-3-carboxylate displayed high antiviral potency, low cellular cytotoxicity, and high in vitro metabolic stability.

A Systematic Survey of Reversibly Covalent Dipeptidyl Inhibitors of the SARS-CoV-2 Main Protease.,Geng ZZ, Atla S, Shaabani N, Vulupala V, Yang KS, Alugubelli YR, Khatua K, Chen PH, Xiao J, Blankenship LR, Ma XR, Vatansever EC, Cho CD, Ma Y, Allen R, Ji H, Xu S, Liu WR J Med Chem. 2023 Aug 24;66(16):11040-11055. doi: 10.1021/acs.jmedchem.3c00221. , Epub 2023 Aug 10. PMID:37561993<ref>PMID:37561993</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8stz" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Severe acute respiratory syndrome coronavirus 2]]
[[Category: Blankenship LB]]
[[Category: Liu WR]]