7pie: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7pie]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Cricetulus_griseus Cricetulus griseus] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7PIE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7PIE FirstGlance]. <br> | <table><tr><td colspan='2'>[[7pie]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Cricetulus_griseus Cricetulus griseus] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7PIE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7PIE FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7QF:2-azanyl-5-[3-[( | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.427Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7QF:2-azanyl-5-[3-[(2~{R})-morpholin-2-yl]phenyl]benzenecarbonitrile'>7QF</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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=7pie FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7pie OCA], [https://pdbe.org/7pie PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7pie RCSB], [https://www.ebi.ac.uk/pdbsum/7pie PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7pie 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=7pie FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7pie OCA], [https://pdbe.org/7pie PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7pie RCSB], [https://www.ebi.ac.uk/pdbsum/7pie PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7pie ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/ | [https://www.uniprot.org/uniprot/IPKA_MOUSE IPKA_MOUSE] Extremely potent competitive inhibitor of cAMP-dependent protein kinase activity, this protein interacts with the catalytic subunit of the enzyme after the cAMP-induced dissociation of its regulatory chains. | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
Fragment-based drug discovery (FBDD) has successfully led to approved therapeutics for challenging and "undruggable" targets. In the context of FBDD, we introduce a novel, multidisciplinary method to identify active molecules from purchasable chemical space. Starting from four small-molecule fragment complexes of protein kinase A (PKA), a template-based docking screen using Enamine's multibillion REAL Space was performed. A total of 93 molecules out of 106 selected compounds were successfully synthesized. Forty compounds were active in at least one validation assay with the most active follow-up having a 13,500-fold gain in affinity. Crystal structures for six of the most promising binders were rapidly obtained, verifying the binding mode. The overall success rate for this novel fragment-to-hit approach was 40%, accomplished in only 9 weeks. The results challenge the established fragment prescreening paradigm since the standard industrial filters for fragment hit identification in a thermal shift assay would have missed the initial fragments. | Fragment-based drug discovery (FBDD) has successfully led to approved therapeutics for challenging and "undruggable" targets. In the context of FBDD, we introduce a novel, multidisciplinary method to identify active molecules from purchasable chemical space. Starting from four small-molecule fragment complexes of protein kinase A (PKA), a template-based docking screen using Enamine's multibillion REAL Space was performed. A total of 93 molecules out of 106 selected compounds were successfully synthesized. Forty compounds were active in at least one validation assay with the most active follow-up having a 13,500-fold gain in affinity. Crystal structures for six of the most promising binders were rapidly obtained, verifying the binding mode. The overall success rate for this novel fragment-to-hit approach was 40%, accomplished in only 9 weeks. The results challenge the established fragment prescreening paradigm since the standard industrial filters for fragment hit identification in a thermal shift assay would have missed the initial fragments. | ||
Magnet for the Needle in Haystack: "Crystal Structure First" Fragment Hits Unlock Active Chemical Matter Using Targeted Exploration of Vast Chemical Spaces.,Muller J, Klein R, Tarkhanova O, Gryniukova A, Borysko P, Merkl S, Ruf M, Neumann A, Gastreich M, Moroz YS, Klebe G, Glinca S J Med Chem. 2022 | Magnet for the Needle in Haystack: "Crystal Structure First" Fragment Hits Unlock Active Chemical Matter Using Targeted Exploration of Vast Chemical Spaces.,Muller J, Klein R, Tarkhanova O, Gryniukova A, Borysko P, Merkl S, Ruf M, Neumann A, Gastreich M, Moroz YS, Klebe G, Glinca S J Med Chem. 2022 Dec 8;65(23):15663-15678. doi: 10.1021/acs.jmedchem.2c00813. , Epub 2022 Sep 7. PMID:36069712<ref>PMID:36069712</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> | ||
Latest revision as of 09:40, 21 November 2024
Protein kinase A catalytic subunit in complex with PKI5-24 and EN068Protein kinase A catalytic subunit in complex with PKI5-24 and EN068
Structural highlights
FunctionIPKA_MOUSE Extremely potent competitive inhibitor of cAMP-dependent protein kinase activity, this protein interacts with the catalytic subunit of the enzyme after the cAMP-induced dissociation of its regulatory chains. Publication Abstract from PubMedFragment-based drug discovery (FBDD) has successfully led to approved therapeutics for challenging and "undruggable" targets. In the context of FBDD, we introduce a novel, multidisciplinary method to identify active molecules from purchasable chemical space. Starting from four small-molecule fragment complexes of protein kinase A (PKA), a template-based docking screen using Enamine's multibillion REAL Space was performed. A total of 93 molecules out of 106 selected compounds were successfully synthesized. Forty compounds were active in at least one validation assay with the most active follow-up having a 13,500-fold gain in affinity. Crystal structures for six of the most promising binders were rapidly obtained, verifying the binding mode. The overall success rate for this novel fragment-to-hit approach was 40%, accomplished in only 9 weeks. The results challenge the established fragment prescreening paradigm since the standard industrial filters for fragment hit identification in a thermal shift assay would have missed the initial fragments. Magnet for the Needle in Haystack: "Crystal Structure First" Fragment Hits Unlock Active Chemical Matter Using Targeted Exploration of Vast Chemical Spaces.,Muller J, Klein R, Tarkhanova O, Gryniukova A, Borysko P, Merkl S, Ruf M, Neumann A, Gastreich M, Moroz YS, Klebe G, Glinca S J Med Chem. 2022 Dec 8;65(23):15663-15678. doi: 10.1021/acs.jmedchem.2c00813. , Epub 2022 Sep 7. PMID:36069712[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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