View source for 8pf4


==Crystal structure of Trypanosoma brucei trypanothione reductase in complex with 4-(((5-((4-fluorophenethyl)carbamoyl)furan-2-yl)methyl)(4-fluorophenyl)carbamoyl)-1-methyl-1-(3-phenylpropyl)piperazin-1-ium==
<StructureSection load='8pf4' size='340' side='right'caption='[[8pf4]], [[Resolution|resolution]] 1.84&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8pf4]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_brucei Trypanosoma brucei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8PF4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8PF4 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]] 1.84&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=YIA:~{N}-(4-fluorophenyl)-~{N}-[[5-[2-(4-fluorophenyl)ethylcarbamoyl]furan-2-yl]methyl]-4-methyl-4-(3-phenylpropyl)-1,4$l^{4}-diazinane-1-carboxamide'>YIA</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=8pf4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8pf4 OCA], [https://pdbe.org/8pf4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8pf4 RCSB], [https://www.ebi.ac.uk/pdbsum/8pf4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8pf4 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q389T8_TRYB2 Q389T8_TRYB2] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Trypanothione reductase (TR) is a suitable target for drug discovery approaches against leishmaniasis, although the identification of potent inhibitors is still challenging. Herein, we harnessed a fragment-based drug discovery (FBDD) strategy to develop new TR inhibitors. Previous crystallographic screening identified fragments 1-3, which provided ideal starting points for a medicinal chemistry campaign. In silico investigations revealed critical hotspots in the TR binding site, guiding our structure- and ligand-based structure-actvity relationship (SAR) exploration that yielded fragment-derived compounds 4-14. A trend of improvement in Leishmania infantum TR inhibition was detected along the optimization and confirmed by the crystal structures of 9, 10, and 14 in complex with Trypanosoma brucei TR. Compound 10 showed the best TR inhibitory profile (K(i) = 0.2 muM), whereas 9 was the best one in terms of in vitro and ex vivo activity. Although further fine-tuning is needed to improve selectivity, we demonstrated the potentiality of FBDD on a classic but difficult target for leishmaniasis.

Fragment Merging, Growing, and Linking Identify New Trypanothione Reductase Inhibitors for Leishmaniasis.,Exertier C, Salerno A, Antonelli L, Fiorillo A, Ocello R, Seghetti F, Caciolla J, Uliassi E, Masetti M, Fiorentino E, Orsini S, Di Muccio T, Ilari A, Bolognesi ML J Med Chem. 2024 Jan 11;67(1):402-419. doi: 10.1021/acs.jmedchem.3c01439. Epub , 2024 Jan 2. PMID:38164929<ref>PMID:38164929</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8pf4" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Trypanosoma brucei]]
[[Category: Antonelli L]]
[[Category: Exertier C]]
[[Category: Fiorillo A]]
[[Category: Ilari A]]