4LXK

Crystal Structure of Human Beta Secretase in Complex with compound 11d

Summary for 4LXK

• Entry DOI: 10.2210/pdb4lxk/pdb
• Related: 4LXA 4LXM
• Descriptor: Beta-secretase 1, (1R,3S,4S,5R)-3-(4-amino-3-fluoro-5-{[(2R)-1,1,1-trifluoro-3-methoxypropan-2-yl]oxy}benzyl)-5-[(3-tert-butylbenzyl)amino]tetrahydro-2H-thiopyran-4-ol 1-oxide, GLYCEROL, ... (4 entities in total)
• Functional Keywords: structure-based drug design, aspartyl protease, membrane, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 3
• Total formula weight: 136106.03

Authors

Rondeau, J.M.,Bourgier, E. (deposition date: 2013-07-30, release date: 2013-08-28, Last modification date: 2024-10-30)

Primary citation

Rueeger, H.,Lueoend, R.,Machauer, R.,Veenstra, S.J.,Jacobson, L.H.,Staufenbiel, M.,Desrayaud, S.,Rondeau, J.M.,Mobitz, H.,Neumann, U.
Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective beta-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid beta-peptides.
Bioorg.Med.Chem.Lett., 23:5300-5306, 2013

PubMed Abstract: Previous structure based optimization in our laboratories led to the identification of a novel, high-affinity cyclic sulfone hydroxyethylamine-derived inhibitor such as 1 that lowers CNS-derived Aβ following oral administration to transgenic APP51/16 mice. Herein we report SAR development in the S3 and S2' subsites of BACE1 for cyclic sulfoxide hydroxyethyl amine inhibitors, the synthetic approaches employed in this effort, and in vivo data for optimized compound such as 11d.

PubMed: 23981898
DOI: 10.1016/j.bmcl.2013.07.071

Experimental method

X-RAY DIFFRACTION (2.05 Å)