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==Improved Feline Drugs as SARS-CoV-2 Mpro Inhibitors: Structure-Activity Studies & Micellar Solubilization for Enhanced Bioavailability==
<StructureSection load='7lco' size='340' side='right'caption='[[7lco]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LCO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LCO 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]] 1.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=XTJ:(3-fluorophenyl)methyl+[(2S)-3-cyclopropyl-1-oxo-1-({(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)propan-2-yl]carbamate'>XTJ</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=7lco FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lco OCA], [https://pdbe.org/7lco PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lco RCSB], [https://www.ebi.ac.uk/pdbsum/7lco PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lco ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Replication of SARS-CoV-2, the coronavirus causing COVID-19, requires a main protease (M(pro)) to cleave viral proteins. Consequently, M(pro) is a target for antiviral agents. We and others previously demonstrated that GC376, a bisulfite prodrug with efficacy as an anti-coronaviral agent in animals, is an effective inhibitor of M(pro) in SARS-CoV-2. Here, we report structure-activity studies of improved GC376 derivatives with nanomolar affinities and therapeutic indices &gt;200. Crystallographic structures of inhibitor-M(pro) complexes reveal that an alternative binding pocket in M(pro), S4, accommodates the P3 position. Alternative binding is induced by polar P3 groups or a nearby methyl. NMR and solubility studies with GC376 show that it exists as a mixture of stereoisomers and forms colloids in aqueous media at higher concentrations, a property not previously reported. Replacement of its Na(+) counter ion with choline greatly increases solubility. The physical, biochemical, crystallographic, and cellular data reveal new avenues for M(pro) inhibitor design.

Improved SARS-CoV-2 M(pro) inhibitors based on feline antiviral drug GC376: Structural enhancements, increased solubility, and micellar studies.,Vuong W, Fischer C, Khan MB, van Belkum MJ, Lamer T, Willoughby KD, Lu J, Arutyunova E, Joyce MA, Saffran HA, Shields JA, Young HS, Nieman JA, Tyrrell DL, Lemieux MJ, Vederas JC Eur J Med Chem. 2021 May 30;222:113584. doi: 10.1016/j.ejmech.2021.113584. PMID:34118724<ref>PMID:34118724</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7lco" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Arutyunova E]]
[[Category: Khan MB]]
[[Category: Lemieux MJ]]
[[Category: Lu J]]
[[Category: Young HS]]