4xry: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4xry]] 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=4XRY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XRY FirstGlance]. <br> | <table><tr><td colspan='2'>[[4xry]] 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=4XRY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XRY FirstGlance]. <br> | ||
</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=SI5:(4AR,6R,8AS)-8A-(2,4-DIFLUOROPHENYL)-6-(1-METHYL-1H-PYRAZOL-4-YL)-4,4A,5,6,8,8A-HEXAHYDROPYRANO[3,4-D][1,3]THIAZIN-2-AMINE'>SI5</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]] 2.5Å</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=SI5:(4AR,6R,8AS)-8A-(2,4-DIFLUOROPHENYL)-6-(1-METHYL-1H-PYRAZOL-4-YL)-4,4A,5,6,8,8A-HEXAHYDROPYRANO[3,4-D][1,3]THIAZIN-2-AMINE'>SI5</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=4xry FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xry OCA], [https://pdbe.org/4xry PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xry RCSB], [https://www.ebi.ac.uk/pdbsum/4xry PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xry ProSAT]</span></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=4xry FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xry OCA], [https://pdbe.org/4xry PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xry RCSB], [https://www.ebi.ac.uk/pdbsum/4xry PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xry ProSAT]</span></td></tr> | ||
</table> | </table> | ||
Latest revision as of 10:48, 27 September 2023
Human Cytochrome P450 2D6 BACE1 Inhibitor 5 ComplexHuman Cytochrome P450 2D6 BACE1 Inhibitor 5 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 PubMedIn recent years, the first generation of beta-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer's disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Herein, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5. Further profiling suggested that a high fraction of the metabolism (>95%) was due to CYP2D6, increasing the potential risk for victim-based drug-drug interactions (DDI) and variable exposure in the clinic due to the polymorphic nature of this enzyme. To guide future design, we solved crystal structures of CYP2D6 complexes with substrate 5 and its corresponding metabolic product pyrazole 6, which provided insight into the binding mode and movements between substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal structures, we designed and synthesized analogs with reduced risk for DDI, central efficacy, and improved hERG therapeutic margins. Utilizing CYP2D6 and BACE1 Structure Complexes to Reduce Risk of Drug-Drug Interactions with a Novel Series of Centrally Efficacious BACE1 Inhibitors.,Brodney MA, Beck EM, Butler CR, Barreiro G, Johnson EF, Riddell D, Parris K, Nolan CE, Fan Y, Atchison K, Gonzales C, Robshaw A, Doran SD, Bundesmann MW, Buzon LM, Dutra JK, Henegar KE, LaChapelle EA, Hou X, Rogers BN, Pandit J, Lira R, Martinez-Alsina LA, Mikochik P, Murray JC, Ogilvie K, Price L, Sakya S, Yu A, Zhang Y, O'Neill BT J Med Chem. 2015 Mar 17. PMID:25781223[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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