4uwi: Difference between revisions
New page: '''Unreleased structure''' The entry 4uwi is ON HOLD Authors: Robinson, D.A., Brand, S., Norcross, N.R., Thompson, S., Harrison, J.R., Smith, V.C., Torrie, L.S., McElroy, S.P., Hallybur... |
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==Crystal structure of Aspergillus fumigatus N-myristoyl transferase in complex with myristoyl CoA and a pyrazole sulphonamide ligand== | |||
<StructureSection load='4uwi' size='340' side='right'caption='[[4uwi]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4uwi]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Aspergillus_fumigatus Aspergillus fumigatus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UWI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4UWI 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=MYA:TETRADECANOYL-COA'>MYA</scene>, <scene name='pdbligand=XMQ:2,6-DICHLORO-4-[3-(4-METHYLPIPERAZIN-1-YL)PROPYL]-N-(1,3,5-TRIMETHYL-1H-PYRAZOL-4-YL)BENZENESULFONAMIDE'>XMQ</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=4uwi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4uwi OCA], [https://pdbe.org/4uwi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4uwi RCSB], [https://www.ebi.ac.uk/pdbsum/4uwi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4uwi ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/NMT_ASPFU NMT_ASPFU] Adds a myristoyl group to the N-terminal glycine residue of certain cellular proteins. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Trypanosoma brucei N-myristoyltransferase (TbNMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis (HAT). From previous studies, we identified pyrazole sulfonamide, DDD85646 (1), a potent inhibitor of TbNMT. Although this compound represents an excellent lead, poor central nervous system (CNS) exposure restricts its use to the hemolymphatic form (stage 1) of the disease. With a clear clinical need for new drug treatments for HAT that address both the hemolymphatic and CNS stages of the disease, a chemistry campaign was initiated to address the shortfalls of this series. This paper describes modifications to the pyrazole sulfonamides which markedly improved blood-brain barrier permeability, achieved by reducing polar surface area and capping the sulfonamide. Moreover, replacing the core aromatic with a flexible linker significantly improved selectivity. This led to the discovery of DDD100097 (40) which demonstrated partial efficacy in a stage 2 (CNS) mouse model of HAT. | |||
Lead Optimization of a Pyrazole Sulfonamide Series of Trypanosoma brucei N-Myristoyltransferase Inhibitors: Identification and Evaluation of CNS Penetrant Compounds as Potential Treatments for Stage 2 Human African Trypanosomiasis.,Brand S, Norcross NR, Thompson S, Harrison JR, Smith VC, Robinson DA, Torrie LS, McElroy SP, Hallyburton I, Norval S, Scullion P, Stojanovski L, Simeons FR, van Aalten D, Frearson JA, Brenk R, Fairlamb AH, Ferguson MA, Wyatt PG, Gilbert IH, Read KD J Med Chem. 2014 Nov 20. PMID:25412409<ref>PMID:25412409</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4uwi" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Aspergillus fumigatus]] | |||
[[Category: Large Structures]] | |||
[[Category: Brand S]] | |||
[[Category: Brenk R]] | |||
[[Category: Fairlamb AH]] | |||
[[Category: Ferguson MAJ]] | |||
[[Category: Frearson JA]] | |||
[[Category: Gilbert IH]] | |||
[[Category: Hallyburton I]] | |||
[[Category: Harrison JR]] | |||
[[Category: McElroy SP]] | |||
[[Category: Norcross NR]] | |||
[[Category: Norval S]] | |||
[[Category: Read KD]] | |||
[[Category: Robinson DA]] | |||
[[Category: Simeons FRC]] | |||
[[Category: Smith VC]] | |||
[[Category: Stojanovski L]] | |||
[[Category: Thompson S]] | |||
[[Category: Torrie LS]] | |||
[[Category: Wyatt PG]] | |||
Latest revision as of 14:24, 9 May 2024
Crystal structure of Aspergillus fumigatus N-myristoyl transferase in complex with myristoyl CoA and a pyrazole sulphonamide ligandCrystal structure of Aspergillus fumigatus N-myristoyl transferase in complex with myristoyl CoA and a pyrazole sulphonamide ligand
Structural highlights
FunctionNMT_ASPFU Adds a myristoyl group to the N-terminal glycine residue of certain cellular proteins. Publication Abstract from PubMedTrypanosoma brucei N-myristoyltransferase (TbNMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis (HAT). From previous studies, we identified pyrazole sulfonamide, DDD85646 (1), a potent inhibitor of TbNMT. Although this compound represents an excellent lead, poor central nervous system (CNS) exposure restricts its use to the hemolymphatic form (stage 1) of the disease. With a clear clinical need for new drug treatments for HAT that address both the hemolymphatic and CNS stages of the disease, a chemistry campaign was initiated to address the shortfalls of this series. This paper describes modifications to the pyrazole sulfonamides which markedly improved blood-brain barrier permeability, achieved by reducing polar surface area and capping the sulfonamide. Moreover, replacing the core aromatic with a flexible linker significantly improved selectivity. This led to the discovery of DDD100097 (40) which demonstrated partial efficacy in a stage 2 (CNS) mouse model of HAT. Lead Optimization of a Pyrazole Sulfonamide Series of Trypanosoma brucei N-Myristoyltransferase Inhibitors: Identification and Evaluation of CNS Penetrant Compounds as Potential Treatments for Stage 2 Human African Trypanosomiasis.,Brand S, Norcross NR, Thompson S, Harrison JR, Smith VC, Robinson DA, Torrie LS, McElroy SP, Hallyburton I, Norval S, Scullion P, Stojanovski L, Simeons FR, van Aalten D, Frearson JA, Brenk R, Fairlamb AH, Ferguson MA, Wyatt PG, Gilbert IH, Read KD J Med Chem. 2014 Nov 20. PMID:25412409[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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