8a3q: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[8a3q]] 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=8A3Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8A3Q FirstGlance]. <br> | <table><tr><td colspan='2'>[[8a3q]] 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=8A3Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8A3Q FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.801Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=8a3q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8a3q OCA], [https://pdbe.org/8a3q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8a3q RCSB], [https://www.ebi.ac.uk/pdbsum/8a3q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8a3q 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=8a3q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8a3q OCA], [https://pdbe.org/8a3q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8a3q RCSB], [https://www.ebi.ac.uk/pdbsum/8a3q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8a3q ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
Hereditary angioedema (HAE) is a rare genetic disorder in which patients experience sudden onset of swelling in various locations of the body. HAE is associated with uncontrolled plasma kallikrein (PKa) enzyme activity and generation of the potent inflammatory mediator, bradykinin, resulting in episodic attacks of angioedema. Herein, we disclose the discovery and optimization of novel small molecule PKa inhibitors. Starting from molecules containing highly basic P1 groups, which typically bind to an aspartic acid residue (Asp189) in the serine protease S1 pocket, we identified novel P1 binding groups likely to have greater potential for oral-drug-like properties. The optimization of P4 and the central core together with the particularly favorable properties of 3-fluoro-4-methoxypyridine P1 led to the development of sebetralstat, a potent, selective, orally bioavailable PKa inhibitor in phase 3 for on-demand treatment of HAE attacks. | Hereditary angioedema (HAE) is a rare genetic disorder in which patients experience sudden onset of swelling in various locations of the body. HAE is associated with uncontrolled plasma kallikrein (PKa) enzyme activity and generation of the potent inflammatory mediator, bradykinin, resulting in episodic attacks of angioedema. Herein, we disclose the discovery and optimization of novel small molecule PKa inhibitors. Starting from molecules containing highly basic P1 groups, which typically bind to an aspartic acid residue (Asp189) in the serine protease S1 pocket, we identified novel P1 binding groups likely to have greater potential for oral-drug-like properties. The optimization of P4 and the central core together with the particularly favorable properties of 3-fluoro-4-methoxypyridine P1 led to the development of sebetralstat, a potent, selective, orally bioavailable PKa inhibitor in phase 3 for on-demand treatment of HAE attacks. | ||
Sebetralstat (KVD900): A Potent and Selective Small Molecule Plasma Kallikrein Inhibitor Featuring a Novel P1 Group as a Potential Oral On-Demand Treatment for Hereditary Angioedema.,Davie RL, Edwards HJ, Evans DM, Hodgson ST, Stocks MJ, Smith AJ, Rushbrooke LJ, Pethen SJ, Roe MB, Clark DE, McEwan PA, Hampton SL J Med Chem. 2022 Oct 27;65(20):13629-13644. doi: 10.1021/acs.jmedchem.2c00921., Epub 2022 Oct 17. PMID:36251573<ref>PMID:36251573</ref> | Sebetralstat (KVD900): A Potent and Selective Small Molecule Plasma Kallikrein Inhibitor Featuring a Novel P1 Group as a Potential Oral On-Demand Treatment for Hereditary Angioedema.,Davie RL, Edwards HJ, Evans DM, Hodgson ST, Stocks MJ, Smith AJ, Rushbrooke LJ, Pethen SJ, Roe MB, Clark DE, McEwan PA, Hampton SL J Med Chem. 2022 Oct 27;65(20):13629-13644. doi: 10.1021/acs.jmedchem.2c00921. , Epub 2022 Oct 17. PMID:36251573<ref>PMID:36251573</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 8a3q" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 8a3q" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Kallikrein 3D structures|Kallikrein 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
Latest revision as of 12:45, 9 October 2024
Human Plasma Kallekrein in complex with 14WHuman Plasma Kallekrein in complex with 14W
Structural highlights
Publication Abstract from PubMedHereditary angioedema (HAE) is a rare genetic disorder in which patients experience sudden onset of swelling in various locations of the body. HAE is associated with uncontrolled plasma kallikrein (PKa) enzyme activity and generation of the potent inflammatory mediator, bradykinin, resulting in episodic attacks of angioedema. Herein, we disclose the discovery and optimization of novel small molecule PKa inhibitors. Starting from molecules containing highly basic P1 groups, which typically bind to an aspartic acid residue (Asp189) in the serine protease S1 pocket, we identified novel P1 binding groups likely to have greater potential for oral-drug-like properties. The optimization of P4 and the central core together with the particularly favorable properties of 3-fluoro-4-methoxypyridine P1 led to the development of sebetralstat, a potent, selective, orally bioavailable PKa inhibitor in phase 3 for on-demand treatment of HAE attacks. Sebetralstat (KVD900): A Potent and Selective Small Molecule Plasma Kallikrein Inhibitor Featuring a Novel P1 Group as a Potential Oral On-Demand Treatment for Hereditary Angioedema.,Davie RL, Edwards HJ, Evans DM, Hodgson ST, Stocks MJ, Smith AJ, Rushbrooke LJ, Pethen SJ, Roe MB, Clark DE, McEwan PA, Hampton SL J Med Chem. 2022 Oct 27;65(20):13629-13644. doi: 10.1021/acs.jmedchem.2c00921. , Epub 2022 Oct 17. PMID:36251573[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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