View source for 8yq8


==Quadruple mutant (N51I+C59R+S108N+I164L) Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS V1/S) complexed with FB8, NADPH and dUMP==
<StructureSection load='8yq8' size='340' side='right'caption='[[8yq8]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8yq8]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_VS/1 Plasmodium falciparum VS/1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8YQ8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8YQ8 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]] 2.1&#8491;</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=8yq8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8yq8 OCA], [https://pdbe.org/8yq8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8yq8 RCSB], [https://www.ebi.ac.uk/pdbsum/8yq8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8yq8 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/D9N170_PLAFA D9N170_PLAFA] Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism (By similarity).[PIRNR:PIRNR000389]
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== Publication Abstract from PubMed ==
As pregnant women and young children remain the first victims of malaria worldwide, the search for new antimalarials has been focusing on compounds with a high safety profile and extended efficacy. In a previous study, a rigid biphenyl PfDHFR inhibitor was developed by fragment-based screening, displaying sub nM enzyme inhibition but poor antiparasitic activity, presumably due to its low flexibility. Here, we report a new series of compounds that combines the biphenyl fragment with a flexible linker. Interestingly, their mode of binding differs from previously reported compounds, taking advantage of strong hydrophobic interaction. The new flexible biphenyl compounds show overall improved antiparasitic activity compared to rigid ones, with the best compound displaying a 2 nM antiplasmodial IC(50) and suitable drug-like properties. This confirms the importance of compound flexibility for antimalarial activity and opens the way to new opportunities for antimalarial drug design.

Novel flexible biphenyl PfDHFR inhibitors with improved antimalarial activity.,Decharuangsilp S, Arwon U, Sooksai N, Rattanajak R, Saeyang T, Vitsupakorn D, Vanichtanankul J, Yuthavong Y, Kamchonwongpaisan S, Hoarau M RSC Med Chem. 2024 May 30;15(7):2496-2507. doi: 10.1039/d4md00197d. eCollection , 2024 Jul 17. PMID:39026651<ref>PMID:39026651</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8yq8" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Plasmodium falciparum VS/1]]
[[Category: Arwon U]]
[[Category: Decharuangsilp S]]
[[Category: Hoarau M]]
[[Category: Kamchonwongpaisan S]]
[[Category: Saeyang T]]
[[Category: Vanichtanankul J]]
[[Category: Vitsupakorn D]]
[[Category: Yuthavong Y]]