9z5l: Difference between revisions
From Proteopedia
Jump to navigationJump to search
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Crystal structure of TgCDPK1 with bound inhibitor== | |||
<StructureSection load='9z5l' size='340' side='right'caption='[[9z5l]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[9z5l]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Toxoplasma_gondii Toxoplasma gondii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9Z5L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9Z5L 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]] 1.8Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1C04:1-[4-(methylamino)cyclohexyl]-3-[4-(trifluoromethyl)pyridin-2-yl]oxy-pyrazolo[3,4-d]pyrimidin-4-amine'>A1C04</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=9z5l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9z5l OCA], [https://pdbe.org/9z5l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9z5l RCSB], [https://www.ebi.ac.uk/pdbsum/9z5l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9z5l ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q9BJF5_TOXGO Q9BJF5_TOXGO] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Toxoplasma gondii is an important opportunistic pathogen that infects many individuals and threatens the health of those with compromised immunity. Current therapies are unable to eradicate chronic infections and pose risks of adverse reactions. Using X-ray structure-based drug design, we have developed a new series of biaryl-substituted pyrazolopyrimidine inhibitors of the essential parasite enzyme calcium-dependent protein kinase 1 (TgCDPK1). These inhibitors have excellent potency against the enzyme and in vitro antiparasitic activity. We further optimized the compounds for increased metabolic stability, lowered plasma protein binding, decreased efflux, and improved pharmacokinetics (PK). Several of the inhibitors had desirable PK with high oral bioavailability, low clearance, and extended half-life, leading to excellent compound exposure in the plasma and brain over a 24-h period. Three compounds were tested during acute infection in both immunocompetent and immunocompromised mice. We identified 16c as a promising preclinical candidate to treat toxoplasmosis. | |||
Lead Optimization of TgCDPK1 Inhibitors for the Treatment of Toxoplasmosis.,Mannino MP, Gokanapalle A, Patil S, Kooner AS, Meena CL, Medcalf M, Vilza I, Barks J, Fu Y, Xia J, Nix JC, Nelson C, Fremont D, Dhillon A, Sibley LD, Janetka JW J Med Chem. 2026 Jun 25;69(12):14365-14389. doi: 10.1021/acs.jmedchem.6c00065. , Epub 2026 Jun 3. PMID:42231809<ref>PMID:42231809</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 9z5l" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Toxoplasma gondii]] | |||
[[Category: Dhillon A]] | |||
[[Category: Fremont D]] | |||
[[Category: Janetka JW]] | |||
[[Category: Nelson C]] | |||
[[Category: Sibley LD]] | |||
Latest revision as of 07:30, 5 August 2026
Crystal structure of TgCDPK1 with bound inhibitor
| ||||||||||||
