5tft: Difference between revisions
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<StructureSection load='5tft' size='340' side='right'caption='[[5tft]], [[Resolution|resolution]] 2.71Å' scene=''> | <StructureSection load='5tft' size='340' side='right'caption='[[5tft]], [[Resolution|resolution]] 2.71Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5tft]] is a 4 chain structure with sequence from [ | <table><tr><td colspan='2'>[[5tft]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TFT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TFT FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=P6U:(4S)-4-[2,4-DIFLUORO-5-({[1-(TRIFLUOROMETHYL)CYCLOPROPYL]AMINO}METHYL)PHENYL]-4-METHYL-5,6-DIHYDRO-4H-1,3-THIAZIN-2-AMINE'>P6U</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.71Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=P6U:(4S)-4-[2,4-DIFLUORO-5-({[1-(TRIFLUOROMETHYL)CYCLOPROPYL]AMINO}METHYL)PHENYL]-4-METHYL-5,6-DIHYDRO-4H-1,3-THIAZIN-2-AMINE'>P6U</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=5tft FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tft OCA], [https://pdbe.org/5tft PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tft RCSB], [https://www.ebi.ac.uk/pdbsum/5tft PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tft ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/CP2D6_HUMAN CP2D6_HUMAN] Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.<ref>PMID:16352597</ref> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Hsu MH]] | |||
[[Category: Hsu | [[Category: Johnson EF]] | ||
[[Category: Johnson | |||
Latest revision as of 15:59, 4 October 2023
Structure of cytochrome P450 2D6 (CYP2D6) BACE1 inhibitor complexStructure of cytochrome P450 2D6 (CYP2D6) BACE1 inhibitor complex
Structural highlights
FunctionCP2D6_HUMAN Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.[1] Publication Abstract from PubMedA growing subset of beta-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) utilizes an anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability and provides a potential metabolic site leading to the formation of an aniline, a structural motif of prospective safety concern. We report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety. Optimization of this series identified analogues with an excellent balance of ADME properties and potency; however, potential drug-drug interactions (DDI) were predicted based on CYP 2D6 affinities. Generation and analysis of key BACE1 and CYP 2D6 crystal structures identified strategies to obviate the DDI liability, leading to compound 16, which exhibits robust in vivo efficacy as a BACE1 inhibitor. Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality.,Butler CR, Ogilvie K, Martinez-Alsina L, Barreiro G, Beck EM, Nolan CE, Atchison K, Benvenuti E, Buzon L, Doran S, Gonzales C, Helal CJ, Hou X, Hsu MH, Johnson EF, Lapham K, Lanyon L, Parris K, O'Neill BT, Riddell D, Robshaw A, Vajdos F, Brodney MA J Med Chem. 2017 Jan 12;60(1):386-402. doi: 10.1021/acs.jmedchem.6b01451. Epub, 2016 Dec 20. PMID:27997172[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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