View source for 4xxs


==Crystal structure of BACE1 with a pyrazole-substituted tetrahydropyran thioamidine==
<StructureSection load='4xxs' size='340' side='right'caption='[[4xxs]], [[Resolution|resolution]] 1.86&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4xxs]] is a 1 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=4XXS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XXS 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]] 1.86&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</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></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=4xxs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xxs OCA], [https://pdbe.org/4xxs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xxs RCSB], [https://www.ebi.ac.uk/pdbsum/4xxs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xxs ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
In 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 (&gt;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<ref>PMID:25781223</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4xxs" style="background-color:#fffaf0;"></div>

==See Also==
*[[Beta secretase 3D structures|Beta secretase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Pandit J]]
[[Category: Parris KD]]