View source for 4frs


==Structure of BACE in complex with (S)-4-(3-chloro-5-(5-(prop-1-yn-1-yl)pyridin-3-yl)thiophen-2-yl)-1,4-dimethyl-6-oxotetrahydropyrimidin-2(1H)-iminium==
<StructureSection load='4frs' size='340' side='right'caption='[[4frs]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4frs]] is a 2 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=4FRS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4FRS 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]] 1.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0V6:(2Z,6S)-6-{3-CHLORO-5-[5-(PROP-1-YN-1-YL)PYRIDIN-3-YL]THIOPHEN-2-YL}-2-IMINO-3,6-DIMETHYLTETRAHYDROPYRIMIDIN-4(1H)-ONE'>0V6</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=4frs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4frs OCA], [https://pdbe.org/4frs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4frs RCSB], [https://www.ebi.ac.uk/pdbsum/4frs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4frs ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/BACE1_HUMAN BACE1_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Inhibition of BACE1 to prevent brain Abeta peptide formation is a potential disease-modifying approach to the treatment of Alzheimer's disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS Abeta levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF Abeta40 levels when administered orally to rats.

Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor that Affords Robust CNS Abeta Reduction.,Stamford AW, Scott JD, Li SW, Babu S, Tadesse D, Hunter R, Wu Y, Misiaszek J, Cumming JN, Gilbert EJ, Huang C, McKittrick BA, Hong L, Guo T, Zhu Z, Strickland C, Orth P, Voigt JH, Kennedy ME, Chen X, Kuvelkar R, Hodgson R, Hyde LA, Cox K, Favreau L, Parker EM, Greenlee WJ ACS Med Chem Lett. 2012 Nov 8;3(11):897-902. Epub 2012 Jul 12. PMID:23412139<ref>PMID:23412139</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4frs" 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: Orth P]]