5hct: Difference between revisions

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~~'''Unreleased structure'''~~

~~The entry~~ 5hct is ~~ON HOLD~~

==Endothiapepsin in complex with biacylhydrazone==

== Structural highlights ==

<table><tr><td colspan='2'>[[5hct]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Cryphonectria_parasitica Cryphonectria parasitica]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HCT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HCT 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]] 1.36Å</td></tr>

<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=61P:2-AMINO-N-{3-[(E)-{2-[(2S)-2-AMINO-3-(1H-INDOL-3-YL)PROPANOYL]HYDRAZINYLIDENE}METHYL]BENZYLIDENE}-3-(1H-INDOL-2-YL)PROPANEHYDRAZIDE+(NON-PREFERRED+NAME)'>61P</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</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=5hct FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hct OCA], [https://pdbe.org/5hct PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hct RCSB], [https://www.ebi.ac.uk/pdbsum/5hct PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hct ProSAT]</span></td></tr>

</table>

== Function ==

[https://www.uniprot.org/uniprot/CARP_CRYPA CARP_CRYPA]

== Publication Abstract from PubMed ==

Fragment-based drug design (FBDD) affords active compounds for biological targets. While there are numerous reports on FBDD by fragment growing/optimization, fragment linking has rarely been reported. Dynamic combinatorial chemistry (DCC) has become a powerful hit-identification strategy for biological targets. We report the synergistic combination of fragment linking and DCC to identify inhibitors of the aspartic protease endothiapepsin. Based on X-ray crystal structures of endothiapepsin in complex with fragments, we designed a library of bis-acylhydrazones and used DCC to identify potent inhibitors. The most potent inhibitor exhibits an IC50 value of 54 nm, which represents a 240-fold improvement in potency compared to the parent hits. Subsequent X-ray crystallography validated the predicted binding mode, thus demonstrating the efficiency of the combination of fragment linking and DCC as a hit-identification strategy. This approach could be applied to a range of biological targets, and holds the potential to facilitate hit-to-lead optimization.

~~Authors~~: Radeva, N., ~~Heine~~, A., Klebe, G.

Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin: Fragment-Based Drug Design Facilitated by Dynamic Combinatorial Chemistry.,Mondal M, Radeva N, Fanlo-Virgos H, Otto S, Klebe G, Hirsch AK Angew Chem Int Ed Engl. 2016 Jul 12. doi: 10.1002/anie.201603074. PMID:27400756<ref>PMID:27400756</ref>

~~Description~~: ~~Endothiapepsin in complex with biacylhydrazone~~

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>

[[Category: ~~Unreleased Structures~~]]

</div>

[[Category: ~~Klebe, G~~]]

[[Category: Heine, A]]

[[Category: Radeva, N]]

==See Also==

*[[Pepsin|Pepsin]]

== References ==

__TOC__

</StructureSection>

[[Category: Cryphonectria parasitica]]

[[Category: Large Structures]]

[[Category: Heine A]]

[[Category: Klebe G]]

[[Category: Radeva N]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5hct is ON HOLD
+==Endothiapepsin in complex with biacylhydrazone==
+<StructureSection load='5hct' size='340' side='right'caption='[[5hct]], [[Resolution|resolution]] 1.36&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5hct]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Cryphonectria_parasitica Cryphonectria parasitica]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HCT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HCT 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]] 1.36&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=61P:2-AMINO-N-{3-[(E)-{2-[(2S)-2-AMINO-3-(1H-INDOL-3-YL)PROPANOYL]HYDRAZINYLIDENE}METHYL]BENZYLIDENE}-3-(1H-INDOL-2-YL)PROPANEHYDRAZIDE+(NON-PREFERRED+NAME)'>61P</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</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=5hct FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hct OCA], [https://pdbe.org/5hct PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hct RCSB], [https://www.ebi.ac.uk/pdbsum/5hct PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hct ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/CARP_CRYPA CARP_CRYPA]
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Fragment-based drug design (FBDD) affords active compounds for biological targets. While there are numerous reports on FBDD by fragment growing/optimization, fragment linking has rarely been reported. Dynamic combinatorial chemistry (DCC) has become a powerful hit-identification strategy for biological targets. We report the synergistic combination of fragment linking and DCC to identify inhibitors of the aspartic protease endothiapepsin. Based on X-ray crystal structures of endothiapepsin in complex with fragments, we designed a library of bis-acylhydrazones and used DCC to identify potent inhibitors. The most potent inhibitor exhibits an IC50 value of 54 nm, which represents a 240-fold improvement in potency compared to the parent hits. Subsequent X-ray crystallography validated the predicted binding mode, thus demonstrating the efficiency of the combination of fragment linking and DCC as a hit-identification strategy. This approach could be applied to a range of biological targets, and holds the potential to facilitate hit-to-lead optimization.
-Authors: Radeva, N., Heine, A., Klebe, G.
+Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin: Fragment-Based Drug Design Facilitated by Dynamic Combinatorial Chemistry.,Mondal M, Radeva N, Fanlo-Virgos H, Otto S, Klebe G, Hirsch AK Angew Chem Int Ed Engl. 2016 Jul 12. doi: 10.1002/anie.201603074. PMID:27400756<ref>PMID:27400756</ref>
-Description: Endothiapepsin in complex with biacylhydrazone
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Klebe, G]]
+<div class="pdbe-citations 5hct" style="background-color:#fffaf0;"></div>
-[[Category: Heine, A]]
-[[Category: Radeva, N]]
+==See Also==
+*[[Pepsin|Pepsin]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Cryphonectria parasitica]]
+[[Category: Large Structures]]
+[[Category: Heine A]]
+[[Category: Klebe G]]
+[[Category: Radeva N]]