6pl2: Difference between revisions
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The | ==TRK-A IN COMPLEX WITH LIGAND 1a== | ||
<StructureSection load='6pl2' size='340' side='right'caption='[[6pl2]], [[Resolution|resolution]] 2.59Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6pl2]] 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=6PL2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PL2 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]] 2.59Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OOM:~{N}-(5-~{tert}-butyl-2-phenyl-pyrazol-3-yl)-2-[[1-(4-hydroxyphenyl)-1,2,3,4-tetrazol-5-yl]sulfanyl]ethanamide'>OOM</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</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=6pl2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pl2 OCA], [https://pdbe.org/6pl2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pl2 RCSB], [https://www.ebi.ac.uk/pdbsum/6pl2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pl2 ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
In silico virtual screening using the ligand-based ROCS approach and the commercially purchasable compound collection from the ZINC database resulted in the identification of distinctly different and novel acetamide core frameworks with series representatives 1a and 2a exhibiting nanomolar affinity in the kinase domain only hTrkA HTRF biochemical assay. Additional experimental validation using the Caliper technology with either the active or inactive kinase conditions demonstrated the leads, 1a and 2a, to preferentially bind the kinase inactive state. X-ray structural analysis of the kinase domain of hTrkA...1a/2a complexes confirmed the kinase, bind the inhibitor leads in the inactive state and to exhibit a type 2 binding mode with the DFG-out and alphaC-helix out conformation. The leads also demonstrated sub-micromolar activity in the full length hTrkA cell-based assay and selectivity against the closely related hTrkB isoform. However, the poor microsomal stability and permeability of the leads is suggestive of a multiparametric lead optimization effort requirement for further progression. | |||
Type 2 inhibitor leads of human tropomyosin receptor kinase (hTrkA).,Subramanian G, Bowen SJ, Zhu Y, Roush N, Zachary T, Javens C, Williams T, Janssen A, Gonzales A Bioorg Med Chem Lett. 2019 Oct 1;29(19):126624. doi: 10.1016/j.bmcl.2019.126624. , Epub 2019 Aug 16. PMID:31444087<ref>PMID:31444087</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6pl2" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[High affinity nerve growth factor receptor|High affinity nerve growth factor receptor]] | |||
*[[Tyrosine kinase receptor 3D structures|Tyrosine kinase receptor 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Subramanian G]] | |||
Latest revision as of 11:14, 17 October 2024
TRK-A IN COMPLEX WITH LIGAND 1aTRK-A IN COMPLEX WITH LIGAND 1a
Structural highlights
Publication Abstract from PubMedIn silico virtual screening using the ligand-based ROCS approach and the commercially purchasable compound collection from the ZINC database resulted in the identification of distinctly different and novel acetamide core frameworks with series representatives 1a and 2a exhibiting nanomolar affinity in the kinase domain only hTrkA HTRF biochemical assay. Additional experimental validation using the Caliper technology with either the active or inactive kinase conditions demonstrated the leads, 1a and 2a, to preferentially bind the kinase inactive state. X-ray structural analysis of the kinase domain of hTrkA...1a/2a complexes confirmed the kinase, bind the inhibitor leads in the inactive state and to exhibit a type 2 binding mode with the DFG-out and alphaC-helix out conformation. The leads also demonstrated sub-micromolar activity in the full length hTrkA cell-based assay and selectivity against the closely related hTrkB isoform. However, the poor microsomal stability and permeability of the leads is suggestive of a multiparametric lead optimization effort requirement for further progression. Type 2 inhibitor leads of human tropomyosin receptor kinase (hTrkA).,Subramanian G, Bowen SJ, Zhu Y, Roush N, Zachary T, Javens C, Williams T, Janssen A, Gonzales A Bioorg Med Chem Lett. 2019 Oct 1;29(19):126624. doi: 10.1016/j.bmcl.2019.126624. , Epub 2019 Aug 16. PMID:31444087[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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