View source for 8dgy


==Structure of MERS 3CL protease in complex with the cyclopropane based inhibitor 16d (high resolution)==
<StructureSection load='8dgy' size='340' side='right'caption='[[8dgy]], [[Resolution|resolution]] 1.65&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8dgy]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Middle_East_respiratory_syndrome-related_coronavirus Middle East respiratory syndrome-related coronavirus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8DGY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DGY 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]] 1.65&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=S9U:[(1~{R},2~{R})-2-(cyclohexylmethyl)cyclopropyl]methyl+~{N}-[(2~{S})-1-[[(1~{S},2~{S})-1-[bis(oxidanyl)-oxidanylidene-$l^{5}-sulfanyl]-1-oxidanyl-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxidanylidene-pentan-2-yl]carbamate'>S9U</scene>, <scene name='pdbligand=SD6:[(1~{R},2~{R})-2-(cyclohexylmethyl)cyclopropyl]methyl+~{N}-[(2~{S})-1-[[(1~{R},2~{S})-1-[bis(oxidanyl)-oxidanylidene-$l^{5}-sulfanyl]-1-oxidanyl-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxidanylidene-pentan-2-yl]carbamate'>SD6</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=8dgy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dgy OCA], [https://pdbe.org/8dgy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dgy RCSB], [https://www.ebi.ac.uk/pdbsum/8dgy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dgy ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The advent of SARS-CoV-2, the causative agent of COVID-19, and its worldwide impact on global health, have provided the impetus for the development of effective countermeasures that can be deployed against the virus, including vaccines, monoclonal antibodies, and direct-acting antivirals (DAAs). Despite these efforts, the current paucity of DAAs has created an urgent need for the creation of an enhanced and diversified portfolio of broadly acting agents with different mechanisms of action that can effectively abrogate viral infection. SARS-CoV-2 3C-like protease (3CL(pro)), an enzyme essential for viral replication, is a validated target for the discovery of SARS-CoV-2 therapeutics. In this report, we describe the structure-guided utilization of the cyclopropane moiety in the design of highly potent inhibitors of SARS-CoV-2 3CL(pro), SARS-CoV-1 3CL(pro), and MERS-CoV 3CL(pro). High-resolution cocrystal structures were used to identify the structural determinants associated with the binding of the inhibitors to the active site of the enzyme and unravel the mechanism of action. Aldehydes 5c and 11c inhibited SARS-CoV-2 replication with EC(50) values of 12 and 11 nM, respectively. Furthermore, the corresponding aldehyde bisulfite adducts 5d and 11d were equipotent with EC(50) values of 13 and 12 nM, respectively. The safety index (SI) values for compounds 5c / 11c and 5d / 11d ranged between 7692 and 9090. Importantly, aldehydes 5c / 11c and bisulfite adducts 5d / 11d potently inhibited MERS-CoV 3CL(pro) with IC(50) values of 80 and 120 nM, and 70 and 70 nM, respectively. Likewise, compounds 5c / 11c and 5d / 11d inhibited SARS-CoV-1 with IC(50) values of 960 and 350 nM and 790 and 240 nM, respectively. Taken together, these studies suggest that the inhibitors described herein have low cytotoxicity and high potency and are promising candidates for further development as broad-spectrum direct-acting antivirals against highly pathogenic coronaviruses.

Broad-Spectrum Cyclopropane-Based Inhibitors of Coronavirus 3C-like Proteases: Biochemical, Structural, and Virological Studies.,Dampalla CS, Nguyen HN, Rathnayake AD, Kim Y, Perera KD, Madden TK, Thurman HA, Machen AJ, Kashipathy MM, Liu L, Battaile KP, Lovell S, Chang KO, Groutas WC ACS Pharmacol Transl Sci. 2022 Dec 28;6(1):181-194. doi: , 10.1021/acsptsci.2c00206. eCollection 2023 Jan 13. PMID:36654747<ref>PMID:36654747</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8dgy" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Middle East respiratory syndrome-related coronavirus]]
[[Category: Battaile KP]]
[[Category: Chamandi SD]]
[[Category: Chang KO]]
[[Category: Groutas WC]]
[[Category: Kim Y]]
[[Category: Liu L]]
[[Category: Lovell S]]
[[Category: Madden TK]]
[[Category: Nguyen HN]]
[[Category: Picard HR]]
[[Category: Thruman HA]]