View source for 6iuo


==Crystal structure of FGFR4 kinase domain in complex with a covalent inhibitor==
<StructureSection load='6iuo' size='340' side='right'caption='[[6iuo]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6iuo]] 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=6IUO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6IUO 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]] 2.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AWX:N-({4-[4-amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-2-yl]phenyl}methyl)prop-2-enamide'>AWX</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=6iuo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6iuo OCA], [https://pdbe.org/6iuo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6iuo RCSB], [https://www.ebi.ac.uk/pdbsum/6iuo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6iuo ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Alterations of fibroblast growth factor receptors (FGFRs) play key roles in numerous cancer progression and development, which makes FGFRs attractive targets in the cancer therapy. In the present study, based on a newly devised FGFR target-specific scoring function, a novel FGFR inhibitor hit was identified through virtual screening. Hit-to-lead optimization was then performed by integrating molecular docking and site-of-metabolism predictions with an array of in vitro evaluations and X-ray cocrystal structure determination, leading to a covalent FGFR inhibitor 15, which showed a highly selective and potent FGFR inhibition profile. Pharmacokinetic assessment, protein kinase profiling, and hERG inhibition evaluation were also conducted, and they confirmed the value of 15 as a lead for further investigation. Overall, this study exemplifies the importance of the integrative use of computational methods and experimental techniques in drug discovery.

Discovery and Development of a Series of Pyrazolo[3,4-d]pyridazinone Compounds as the Novel Covalent Fibroblast Growth Factor Receptor Inhibitors by the Rational Drug Design.,Wang Y, Dai Y, Wu X, Li F, Liu B, Li C, Liu Q, Zhou Y, Wang B, Zhu M, Cui R, Tan X, Xiong Z, Liu J, Tan M, Xu Y, Geng M, Jiang H, Liu H, Ai J, Zheng M J Med Chem. 2019 Aug 22;62(16):7473-7488. doi: 10.1021/acs.jmedchem.9b00510. Epub, 2019 Aug 9. PMID:31335138<ref>PMID:31335138</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6iuo" style="background-color:#fffaf0;"></div>

==See Also==
*[[Fibroblast growth factor receptor 3D receptor|Fibroblast growth factor receptor 3D receptor]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Liu Q]]
[[Category: Xu Y]]