7zyj: Difference between revisions

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 == Structural highlights ==
 <table><tr><td colspan='2'>[[7zyj]] is a 20 chain structure with sequence from [https://en.wikipedia.org/wiki/Leishmania_tarentolae Leishmania tarentolae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7ZYJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ZYJ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=KFC:~{N}-cyclopentyl-6-methyl-4-phenylazanyl-quinoline-2-carboxamide'>KFC</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=KFC:~{N}-cyclopentyl-6-methyl-4-phenylazanyl-quinoline-2-carboxamide'>KFC</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=7zyj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7zyj OCA], [https://pdbe.org/7zyj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7zyj RCSB], [https://www.ebi.ac.uk/pdbsum/7zyj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7zyj ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/A0A640KBV2_LEITA A0A640KBV2_LEITA]] The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH.[RuleBase:RU000551]
+[https://www.uniprot.org/uniprot/A0A640KZP5_LEITA A0A640KZP5_LEITA] The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH.[RuleBase:RU000551]
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
-Human African Trypanosomiasis (HAT) is a vector-borne disease caused by kinetoplastid parasites of the Trypanosoma genus. The disease proceeds in two stages, with a hemolymphatic blood stage and a meningo-encephalic brain stage. In the latter stage, the parasite causes irreversible damage to the brain leading to sleep cycle disruption and is fatal if untreated. An orally bioavailable treatment is highly desirable. In this study, we present a brain-penetrant, parasite-selective 20S proteasome inhibitor that was rapidly optimized from an HTS singleton hit to drug candidate compound 7 that showed cure in a stage II mouse efficacy model. Here, we describe hit expansion and lead optimization campaign guided by cryo-electron microscopy and an in silico model to predict the brain-to-plasma partition coefficient Kp as an important parameter to prioritize compounds for synthesis. The model combined with in vitro and in vivo experiments allowed us to advance compounds with favorable unbound brain-to-plasma ratios (Kp,uu) to cure a CNS disease such as HAT.
+Human African Trypanosomiasis (HAT) is a vector-borne disease caused by kinetoplastid parasites of the Trypanosoma genus. The disease proceeds in two stages, with a hemolymphatic blood stage and a meningo-encephalic brain stage. In the latter stage, the parasite causes irreversible damage to the brain leading to sleep cycle disruption and is fatal if untreated. An orally bioavailable treatment is highly desirable. In this study, we present a brain-penetrant, parasite-selective 20S proteasome inhibitor that was rapidly optimized from an HTS singleton hit to drug candidate compound 7 that showed cure in a stage II mouse efficacy model. Here, we describe hit expansion and lead optimization campaign guided by cryo-electron microscopy and an in silico model to predict the brain-to-plasma partition coefficient K(p) as an important parameter to prioritize compounds for synthesis. The model combined with in vitro and in vivo experiments allowed us to advance compounds with favorable unbound brain-to-plasma ratios (K(p,uu)) to cure a CNS disease such as HAT.
-Discovery of Novel Quinoline-Based Proteasome Inhibitors for Human African Trypanosomiasis (HAT).,Koester DC, Marx VM, Williams S, Jiricek J, Dauphinais M, Rene O, Miller SL, Zhang L, Patra D, Chen YL, Cheung H, Gable J, Lakshminarayana SB, Osborne C, Galarneau JR, Kulkarni U, Richmond W, Bretz A, Xiao L, Supek F, Wiesmann C, Honnappa S, Be C, Maser P, Kaiser M, Ritchie R, Barrett MP, Diagana TT, Sarko C, Rao SPS J Med Chem. 2022 Sep 8;65(17):11776-11787. doi: 10.1021/acs.jmedchem.2c00791., Epub 2022 Aug 22. PMID:35993839<ref>PMID:35993839</ref>
+Discovery of Novel Quinoline-Based Proteasome Inhibitors for Human African Trypanosomiasis (HAT).,Koester DC, Marx VM, Williams S, Jiricek J, Dauphinais M, Rene O, Miller SL, Zhang L, Patra D, Chen YL, Cheung H, Gable J, Lakshminarayana SB, Osborne C, Galarneau JR, Kulkarni U, Richmond W, Bretz A, Xiao L, Supek F, Wiesmann C, Honnappa S, Be C, Maser P, Kaiser M, Ritchie R, Barrett MP, Diagana TT, Sarko C, Rao SPS J Med Chem. 2022 Sep 8;65(17):11776-11787. doi: 10.1021/acs.jmedchem.2c00791. , Epub 2022 Aug 22. PMID:35993839<ref>PMID:35993839</ref>
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
 <div class="pdbe-citations 7zyj" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Proteasome 3D structures|Proteasome 3D structures]]
 == References ==
 <references/>