7b1e: Difference between revisions
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==BACE1 IN COMPLEX WITH compound 3 (NB-641)== | ==BACE1 IN COMPLEX WITH compound 3 (NB-641)== | ||
<StructureSection load='7b1e' size='340' side='right'caption='[[7b1e]]' scene=''> | <StructureSection load='7b1e' size='340' side='right'caption='[[7b1e]], [[Resolution|resolution]] 1.62Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7B1E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7B1E FirstGlance]. <br> | <table><tr><td colspan='2'>[[7b1e]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7B1E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7B1E FirstGlance]. <br> | ||
</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=7b1e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7b1e OCA], [https://pdbe.org/7b1e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7b1e RCSB], [https://www.ebi.ac.uk/pdbsum/7b1e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7b1e ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SKW:~{N}-[3-[(4~{S})-2-azanyl-4-methyl-5,6-dihydro-1,3-thiazin-4-yl]phenyl]-5-bromanyl-pyridine-2-carboxamide'>SKW</scene></td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </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=7b1e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7b1e OCA], [https://pdbe.org/7b1e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7b1e RCSB], [https://www.ebi.ac.uk/pdbsum/7b1e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7b1e ProSAT]</span></td></tr> | |||
</table> | </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 == | |||
Starting from lead compound 4, the 1,4-oxazine headgroup was optimized to improve potency and brain penetration. Focusing at the 6-position of the 5-amino-1,4-oxazine, the insertion of a Me and a CF3 group delivered an excellent pharmacological profile with a pKa of 7.1 and a very low P-gp efflux ratio enabling high central nervous system (CNS) penetration and exposure. Various synthetic routes to access BACE1 inhibitors bearing a 5-amino-6-methyl-6-(trifluoromethyl)-1,4-oxazine headgroup were investigated. Subsequent optimization of the P3 fragment provided the highly potent N-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin- 3-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide 54 (NB-360), able to reduce significantly Abeta levels in mice, rats, and dogs in acute and chronic treatment regimens. | |||
Synthesis of the Potent, Selective, and Efficacious beta-Secretase (BACE1) Inhibitor NB-360.,Rueeger H, Lueoend R, Machauer R, Veenstra SJ, Holzer P, Hurth K, Voegtle M, Frederiksen M, Rondeau JM, Tintelnot-Blomley M, Jacobson LH, Staufenbiel M, Laue G, Neumann U J Med Chem. 2021 Apr 22;64(8):4677-4696. doi: 10.1021/acs.jmedchem.0c02143. Epub , 2021 Apr 12. PMID:33844524<ref>PMID:33844524</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7b1e" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Rondeau | [[Category: Memapsin 2]] | ||
[[Category: Wirth E]] | [[Category: Rondeau, J M]] | ||
[[Category: Wirth, E]] | |||
[[Category: Alzheimer's disease]] | |||
[[Category: Aspartic acid proteinase]] | |||
[[Category: Bace1]] | |||
[[Category: Beta-secretase]] | |||
[[Category: Enzyme inhibitor complex]] | |||
[[Category: Hydrolase]] | |||
[[Category: Memapsin2]] | |||
[[Category: Structure-based drug design]] | |||