8aof: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[8aof]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8AOF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AOF FirstGlance]. <br> | <table><tr><td colspan='2'>[[8aof]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8AOF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AOF FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=N4U:~{N}-(2-methylpyrimidin-5-yl)propanamide'>N4U</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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]] 1.615Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=N4U:~{N}-(2-methylpyrimidin-5-yl)propanamide'>N4U</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=8aof FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8aof OCA], [https://pdbe.org/8aof PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8aof RCSB], [https://www.ebi.ac.uk/pdbsum/8aof PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8aof 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=8aof FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8aof OCA], [https://pdbe.org/8aof PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8aof RCSB], [https://www.ebi.ac.uk/pdbsum/8aof PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8aof ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
Fragment-based drug discovery (FBDD) has become an established method for the identification of efficient starting points for drug discovery programs. In recent years, electrophilic fragment screening has garnered increased attention from both academia and industry to identify novel covalent hits for tool compound or drug development against challenging drug targets. Herein, we describe the design and characterization of an acrylamide-focused electrophilic fragment library and screening campaign against extracellular signal-regulated kinase 2 (ERK2) using high-throughput protein crystallography as the primary hit-finding technology. Several fragments were found to have covalently modified the adenosine triphosphate (ATP) binding pocket Cys166 residue. From these hits, 22, a covalent ATP-competitive inhibitor with improved potency (ERK2 | Fragment-based drug discovery (FBDD) has become an established method for the identification of efficient starting points for drug discovery programs. In recent years, electrophilic fragment screening has garnered increased attention from both academia and industry to identify novel covalent hits for tool compound or drug development against challenging drug targets. Herein, we describe the design and characterization of an acrylamide-focused electrophilic fragment library and screening campaign against extracellular signal-regulated kinase 2 (ERK2) using high-throughput protein crystallography as the primary hit-finding technology. Several fragments were found to have covalently modified the adenosine triphosphate (ATP) binding pocket Cys166 residue. From these hits, 22, a covalent ATP-competitive inhibitor with improved potency (ERK2 IC(50) = 7.8 muM), was developed. | ||
X-ray Screening of an Electrophilic Fragment Library and Application toward the Development of a Novel ERK 1/2 Covalent Inhibitor.,St Denis JD, Chessari G, Cleasby A, Cons BD, Cowan S, Dalton SE, East C, Murray CW, O'Reilly M, Peakman T, Rapti M, Stow JL J Med Chem. 2022 Sep 22;65(18):12319-12333. doi: 10.1021/acs.jmedchem.2c01044., Epub 2022 Sep 13. PMID:36101934<ref>PMID:36101934</ref> | X-ray Screening of an Electrophilic Fragment Library and Application toward the Development of a Novel ERK 1/2 Covalent Inhibitor.,St Denis JD, Chessari G, Cleasby A, Cons BD, Cowan S, Dalton SE, East C, Murray CW, O'Reilly M, Peakman T, Rapti M, Stow JL J Med Chem. 2022 Sep 22;65(18):12319-12333. doi: 10.1021/acs.jmedchem.2c01044. , Epub 2022 Sep 13. PMID:36101934<ref>PMID:36101934</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> | ||
</div> | </div> | ||
<div class="pdbe-citations 8aof" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 8aof" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Mitogen-activated protein kinase 3D structures|Mitogen-activated protein kinase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
Latest revision as of 12:27, 17 October 2024
Specific covalent inhibitor(16) of ERK2Specific covalent inhibitor(16) of ERK2
Structural highlights
Publication Abstract from PubMedFragment-based drug discovery (FBDD) has become an established method for the identification of efficient starting points for drug discovery programs. In recent years, electrophilic fragment screening has garnered increased attention from both academia and industry to identify novel covalent hits for tool compound or drug development against challenging drug targets. Herein, we describe the design and characterization of an acrylamide-focused electrophilic fragment library and screening campaign against extracellular signal-regulated kinase 2 (ERK2) using high-throughput protein crystallography as the primary hit-finding technology. Several fragments were found to have covalently modified the adenosine triphosphate (ATP) binding pocket Cys166 residue. From these hits, 22, a covalent ATP-competitive inhibitor with improved potency (ERK2 IC(50) = 7.8 muM), was developed. X-ray Screening of an Electrophilic Fragment Library and Application toward the Development of a Novel ERK 1/2 Covalent Inhibitor.,St Denis JD, Chessari G, Cleasby A, Cons BD, Cowan S, Dalton SE, East C, Murray CW, O'Reilly M, Peakman T, Rapti M, Stow JL J Med Chem. 2022 Sep 22;65(18):12319-12333. doi: 10.1021/acs.jmedchem.2c01044. , Epub 2022 Sep 13. PMID:36101934[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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