8fiw: Difference between revisions
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<table><tr><td colspan='2'>[[8fiw]] 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=8FIW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FIW FirstGlance]. <br> | <table><tr><td colspan='2'>[[8fiw]] 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=8FIW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FIW 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]] 2.54Å</td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.54Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Y0E:N-( | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Y0E:~{N}-[(1~{R})-2-oxidanylidene-2-[[(1~{S})-1-phenylethyl]amino]-1-pyridin-3-yl-ethyl]-~{N}-(4-phenylphenyl)prop-2-enamide'>Y0E</scene>, <scene name='pdbligand=Y1E:~{N}-[(1~{S})-2-oxidanylidene-2-[[(1~{S})-1-phenylethyl]amino]-1-pyridin-3-yl-ethyl]-~{N}-(4-phenylphenyl)prop-2-enamide'>Y1E</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=8fiw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fiw OCA], [https://pdbe.org/8fiw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fiw RCSB], [https://www.ebi.ac.uk/pdbsum/8fiw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fiw ProSAT]</span></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=8fiw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fiw OCA], [https://pdbe.org/8fiw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fiw RCSB], [https://www.ebi.ac.uk/pdbsum/8fiw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fiw ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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SARS-CoV-2 main protease (M(pro)) is a validated antiviral drug target of nirmatrelvir, the active ingredient in Pfizer's oral drug Paxlovid. Drug-drug interactions limit the use of Paxlovid. In addition, drug-resistant M(pro) mutants against nirmatrelvir have been identified from cell culture viral passage and naturally occurring variants. As such, there is a need for a second generation of M(pro) inhibitors. In this study, we explored several reactive warheads in the design of M(pro) inhibitors. We identified Jun11119R (vinyl sulfonamide warhead), Jun10221R (propiolamide warhead), Jun1112R (4-chlorobut-2-ynamide warhead), Jun10541R (nitrile warhead), and Jun10963R (dually activated nitrile warhead) as potent M(pro) inhibitors. Jun10541R and Jun10963R also had potent antiviral activity against SARS-CoV-2 in Calu-3 cells with EC(50) values of 2.92 and 6.47 muM, respectively. X-ray crystal structures of M(pro) with Jun10541R and Jun10221 revealed covalent modification of Cys145. These M(pro) inhibitors with diverse reactive warheads collectively represent promising candidates for further development. | SARS-CoV-2 main protease (M(pro)) is a validated antiviral drug target of nirmatrelvir, the active ingredient in Pfizer's oral drug Paxlovid. Drug-drug interactions limit the use of Paxlovid. In addition, drug-resistant M(pro) mutants against nirmatrelvir have been identified from cell culture viral passage and naturally occurring variants. As such, there is a need for a second generation of M(pro) inhibitors. In this study, we explored several reactive warheads in the design of M(pro) inhibitors. We identified Jun11119R (vinyl sulfonamide warhead), Jun10221R (propiolamide warhead), Jun1112R (4-chlorobut-2-ynamide warhead), Jun10541R (nitrile warhead), and Jun10963R (dually activated nitrile warhead) as potent M(pro) inhibitors. Jun10541R and Jun10963R also had potent antiviral activity against SARS-CoV-2 in Calu-3 cells with EC(50) values of 2.92 and 6.47 muM, respectively. X-ray crystal structures of M(pro) with Jun10541R and Jun10221 revealed covalent modification of Cys145. These M(pro) inhibitors with diverse reactive warheads collectively represent promising candidates for further development. | ||
Exploring diverse reactive warheads for the design of SARS-CoV-2 main protease inhibitors.,Tan B, Sacco M, Tan H, Li K, Joyce R, Zhang X, Chen Y, Wang J Eur J Med Chem. 2023 | Exploring diverse reactive warheads for the design of SARS-CoV-2 main protease inhibitors.,Tan B, Sacco M, Tan H, Li K, Joyce R, Zhang X, Chen Y, Wang J Eur J Med Chem. 2023 Nov 5;259:115667. doi: 10.1016/j.ejmech.2023.115667. Epub , 2023 Jul 19. PMID:37482021<ref>PMID:37482021</ref> | ||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
