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| | ==Structure of cytochrome P450 2D6 (CYP2D6) BACE1 inhibitor complex== | | ==Structure of cytochrome P450 2D6 (CYP2D6) BACE1 inhibitor complex== |
| - | <StructureSection load='5tfu' size='340' side='right' caption='[[5tfu]], [[Resolution|resolution]] 2.75Å' scene=''> | + | <StructureSection load='5tfu' size='340' side='right'caption='[[5tfu]], [[Resolution|resolution]] 2.75Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5tfu]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TFU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TFU FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5tfu]] 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=5TFU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TFU 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=P6M:(4S,6R)-4-[2,4-DIFLUORO-5-({[1-(TRIFLUOROMETHYL)CYCLOPROPYL]AMINO}METHYL)PHENYL]-4,6-DIMETHYL-5,6-DIHYDRO-4H-1,3-THIAZIN-2-AMINE'>P6M</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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]] 2.75Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5tft|5tft]]</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=P6M:(4S,6R)-4-[2,4-DIFLUORO-5-({[1-(TRIFLUOROMETHYL)CYCLOPROPYL]AMINO}METHYL)PHENYL]-4,6-DIMETHYL-5,6-DIHYDRO-4H-1,3-THIAZIN-2-AMINE'>P6M</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP2D6, CYP2DL1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5tfu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tfu OCA], [https://pdbe.org/5tfu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tfu RCSB], [https://www.ebi.ac.uk/pdbsum/5tfu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tfu ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Unspecific_monooxygenase Unspecific monooxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.14.1 1.14.14.1] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5tfu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tfu OCA], [http://pdbe.org/5tfu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tfu RCSB], [http://www.ebi.ac.uk/pdbsum/5tfu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tfu ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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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| | </div> | | </div> |
| | <div class="pdbe-citations 5tfu" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5tfu" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Unspecific monooxygenase]] | + | [[Category: Large Structures]] |
| - | [[Category: Hsu, M H]] | + | [[Category: Hsu MH]] |
| - | [[Category: Johnson, E F]] | + | [[Category: Johnson EF]] |
| - | [[Category: Bace1]]
| + | |
| - | [[Category: Cyp2d6]]
| + | |
| - | [[Category: Cytochrome p450]]
| + | |
| - | [[Category: Monooxygenase]]
| + | |
| - | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
| + | |
| - | [[Category: P450 2d6]]
| + | |
| Structural highlights
Function
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.[1]
Publication Abstract from PubMed
A 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 Also
References
- ↑ Rowland P, Blaney FE, Smyth MG, Jones JJ, Leydon VR, Oxbrow AK, Lewis CJ, Tennant MG, Modi S, Eggleston DS, Chenery RJ, Bridges AM. Crystal structure of human cytochrome P450 2D6. J Biol Chem. 2006 Mar 17;281(11):7614-22. Epub 2005 Dec 13. PMID:16352597 doi:http://dx.doi.org/10.1074/jbc.M511232200
- ↑ 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. Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality. J Med Chem. 2017 Jan 12;60(1):386-402. doi: 10.1021/acs.jmedchem.6b01451. Epub, 2016 Dec 20. PMID:27997172 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01451
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