4D83

Crystal Structure of Human Beta Secretase in Complex with NVP-BUR436, derived from a co-crystallization experiment

Summary for 4D83

• Entry DOI: 10.2210/pdb4d83/pdb
• Related: 3VEU 3VF3 3VG1 4D85 4D88 4D89 4D8C
• Descriptor: Beta-secretase 1, (3R,4S,5S)-3-[(3-tert-butylbenzyl)amino]-5-{[3-(2,2-difluoroethyl)-1H-indol-5-yl]methyl}tetrahydro-2H-thiopyran-4-ol 1,1-dioxide (3 entities in total)
• Functional Keywords: beta-secretase, memapsin2, bace1, aspartic proteinase, alzheimer's disease, enzyme inhibitor complex, structure-based drug design, 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: 135845.90

Authors

Rondeau, J.M.,Bourgier, E. (deposition date: 2012-01-10, release date: 2012-11-21, Last modification date: 2024-11-06)

Primary citation

Rueeger, H.,Lueoend, R.,Rogel, O.,Rondeau, J.M.,Mobitz, H.,Machauer, R.,Jacobson, L.,Staufenbiel, M.,Desrayaud, S.,Neumann, U.
Discovery of cyclic sulfone hydroxyethylamines as potent and selective beta-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid beta-peptides
J.Med.Chem., 55:3364-3386, 2012

PubMed Abstract: Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure-activity relationship development were supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with central nervous system drugs led to inhibitors with improved blood-brain barrier permeability. Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC(50) values of 2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APP51/16 transgenic mice at oral doses of 180 μmol/kg demonstrated significant reduction of brain Aβ levels.

PubMed: 22380629
DOI: 10.1021/jm300069y

Experimental method

X-RAY DIFFRACTION (2.4 Å)