9tm2: Difference between revisions

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'''Unreleased structure'''


The entry 9tm2 is ON HOLD  until Paper Publication
==Plasmodium falciparum dihydroorotate dehydrogenase in complex with 3-hydroxy-1-methyl pyrazole derivatives==
<StructureSection load='9tm2' size='340' side='right'caption='[[9tm2]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9tm2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9TM2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9TM2 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]] 2.4&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JWQ:5-[(3-~{tert}-butylphenoxy)methyl]-1-methyl-3-oxidanyl-pyrazole-4-carboxylic+acid'>A1JWQ</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</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=9tm2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9tm2 OCA], [https://pdbe.org/9tm2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9tm2 RCSB], [https://www.ebi.ac.uk/pdbsum/9tm2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9tm2 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PYRD_PLAF7 PYRD_PLAF7] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Malaria remains one of the world's most devastating parasitic diseases, with increasing resistance to current therapies highlighting the need for new antimalarial agents with novel mechanisms of action. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH), a key enzyme in pyrimidine biosynthesis, represents a validated molecular target for antimalarial drug discovery. In this study, a structure-based optimization strategy was applied to a previously identified hydroxypyrazole hit compound to design, synthesize, and evaluate new derivatives as selective PfDHODH inhibitors. Through three iterative rounds of rational design, we identified several analogs with notable PfDHODH activity and, in some cases, selectivity over the human isoform (SI &gt; 30). X-ray crystallographic studies of PfDHODH in complex with the most active inhibitors confirmed their predicted binding modes and demonstrated the enzyme's ability to accommodate bulky hydrophobic substituents. The best compounds, notably derivatives 6, 7, 12, 13 and 22, exhibited low micromolar enzymatic inhibition (IC(50) values from 1.3 to 5.9 muM), favourable physicochemical properties (PBS solubility 0.03 - 2.8 mM, logD(7.4) 0.25 - 1.7), and antiparasitic activity in P. falciparum 3D7 cultures (EC(50) values from 15 to 22 muM), with negligible cytotoxicity in mammalian cells (CC(50) &gt; 150 muM except for compound 22). While these hydroxypyrazole-based scaffolds have poor antiplasmodial activity, this study provides structure activity relationship data that may be useful for the development of next-generation PfDHODH inhibitors for malaria chemoprevention and treatment.


Authors: Alberti, M., Miggiano, R.
Structure-based design of new pyrazole inhibitors targeting Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH).,Pippione AC, Villella N, Fornaseri F, Giorgis M, Sharma M, Rolando B, Sainas S, Salamanca E, Gimenez A, Cojean S, Vyas VK, Buccinna B, Ramondetti C, Piccinini M, Poli G, Tuccinardi T, Alberti M, Miggiano R, Lolli ML, Boschi D Eur J Med Chem. 2026 Mar 7;309:118753. doi: 10.1016/j.ejmech.2026.118753. PMID:41855879<ref>PMID:41855879</ref>


Description: Plasmodium falciparum dihydroorotate dehydrogenase in complex with 3-hydroxy-1-methyl pyrazole derivatives
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
[[Category: Miggiano, R]]
<div class="pdbe-citations 9tm2" style="background-color:#fffaf0;"></div>
[[Category: Alberti, M]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Plasmodium falciparum]]
[[Category: Alberti M]]
[[Category: Miggiano R]]
Retrieved from "https://proteopedia.org/9tm2"