7nqo: Difference between revisions
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==Mycobacterium tuberculosis Cytochrome P450 CYP121 in complex with lead compound 21== | ==Mycobacterium tuberculosis Cytochrome P450 CYP121 in complex with lead compound 21== | ||
<StructureSection load='7nqo' size='340' side='right'caption='[[7nqo]]' scene=''> | <StructureSection load='7nqo' size='340' side='right'caption='[[7nqo]], [[Resolution|resolution]] 1.60Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NQO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NQO FirstGlance]. <br> | <table><tr><td colspan='2'>[[7nqo]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NQO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NQO FirstGlance]. <br> | ||
</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=7nqo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nqo OCA], [https://pdbe.org/7nqo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nqo RCSB], [https://www.ebi.ac.uk/pdbsum/7nqo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nqo ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=HEC:HEME+C'>HEC</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ULZ:4-[4-[2-(5-bromanyl-1~{H}-indol-3-yl)ethyl]pyrimidin-2-yl]morpholine'>ULZ</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=7nqo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nqo OCA], [https://pdbe.org/7nqo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nqo RCSB], [https://www.ebi.ac.uk/pdbsum/7nqo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nqo ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/CP121_MYCTU CP121_MYCTU] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
There is a pressing need for new drugs against tuberculosis (TB) to combat the growing resistance to current antituberculars. Herein a novel strategy is described for hit generation against promising TB targets involving X-ray crystallographic screening in combination with phenotypic screening. This combined approach (XP Screen) affords both a validation of target engagement as well as determination of in cellulo activity. The utility of this method is illustrated by way of an XP Screen against CYP121A1, a cytochrome P450 enzyme from Mycobacterium tuberculosis (Mtb) championed as a validated drug discovery target. A focused screening set was synthesized and tested by such means, with several members of the set showing promising activity against Mtb strain H37Rv. One compound was observed as an X-ray hit against CYP121A1 and showed improved activity against Mtb strain H37Rv under multiple assay conditions (pan-assay activity). Data obtained during X-ray crystallographic screening were utilized in a structure-based campaign to design a limited number of analogues (less than twenty), many of which also showed pan-assay activity against Mtb strain H37Rv. These included the benzo[b][1,4]oxazine derivative (MIC90 6.25 muM), a novel hit compound suitable as a starting point for a more involved hit to lead candidate medicinal chemistry campaign. | |||
A new strategy for hit generation: Novel in cellulo active inhibitors of CYP121A1 from Mycobacterium tuberculosis via a combined X-ray crystallographic and phenotypic screening approach (XP screen).,Frederickson M, Selvam IR, Evangelopoulos D, McLean KJ, Katariya MM, Tunnicliffe RB, Campbell B, Kavanagh ME, Charoensutthivarakul S, Blankley RT, Levy CW, de Carvalho LPS, Leys D, Munro AW, Coyne AG, Abell C Eur J Med Chem. 2022 Jan 11;230:114105. doi: 10.1016/j.ejmech.2022.114105. PMID:35065413<ref>PMID:35065413</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7nqo" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Mycobacterium tuberculosis H37Rv]] | |||
[[Category: Selvam IR]] | [[Category: Selvam IR]] | ||