View source for 6x82


==Crystal Structure of TNFalpha with isoquinoline compound 4==
<StructureSection load='6x82' size='340' side='right'caption='[[6x82]], [[Resolution|resolution]] 2.75&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6X82 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6X82 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]] 2.75&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=UTM:8-[4-(2-{5-[(4-methylpiperazin-1-yl)methyl]-2-(1H-pyrrolo[3,2-c]pyridin-3-yl)phenoxy}ethyl)phenyl]isoquinoline'>UTM</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=6x82 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6x82 OCA], [https://pdbe.org/6x82 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6x82 RCSB], [https://www.ebi.ac.uk/pdbsum/6x82 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6x82 ProSAT]</span></td></tr>
</table>
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== Publication Abstract from PubMed ==
Tumor necrosis factor alpha (TNFalpha) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-kappaB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFalpha has led to improved clinical outcomes for patients with rheumatoid arthritis and other chronic autoimmune diseases; however, TNFalpha has proven to be difficult to drug with small molecules. Herein, we present a two-phase, fragment-based drug discovery (FBDD) effort in which we first identified isoquinoline fragments that disrupt TNFalpha ligand-receptor binding through an allosteric desymmetrization mechanism as observed in high-resolution crystal structures. The second phase of discovery focused on the de novo design and optimization of fragments with improved binding efficiency and drug-like properties. The 3-indolinone-based lead presented here displays oral, in vivo efficacy in a mouse glucose-6-phosphate isomerase (GPI)-induced paw swelling model comparable to that seen with a TNFalpha antibody.

Development of Orally Efficacious Allosteric Inhibitors of TNFalpha via Fragment-Based Drug Design.,Dietrich JD, Longenecker KL, Wilson NS, Goess C, Panchal SC, Swann SL, Petros AM, Hobson AD, Ihle D, Song D, Richardson P, Comess KM, Cox PB, Dombrowski A, Sarris K, Donnelly-Roberts DL, Duignan DB, Gomtsyan A, Jung P, Krueger AC, Mathieu S, McClure A, Stoll VS, Wetter J, Mankovich JA, Hajduk PJ, Vasudevan A, Stoffel RH, Sun C J Med Chem. 2020 Dec 30. doi: 10.1021/acs.jmedchem.0c01280. PMID:33378180<ref>PMID:33378180</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6x82" style="background-color:#fffaf0;"></div>

==See Also==
*[[Tumor necrosis factor 3D structures|Tumor necrosis factor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Longenecker KL]]
[[Category: Stoll VS]]