3PI5

Crystal Structure of Human Beta Secretase in Complex with BFG356

Summary for 3PI5

• Entry DOI: 10.2210/pdb3pi5/pdb
• Descriptor: Beta-secretase 1, (3S,4S,5R)-3-(3-bromo-4-hydroxybenzyl)-5-[(3-cyclopropylbenzyl)amino]tetrahydro-2H-thiopyran-4-ol 1,1-dioxide (3 entities in total)
• Functional Keywords: enzyme inhibitor complex, aspartic proteinase, 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: 135773.25

Authors

Rondeau, J.M. (deposition date: 2010-11-05, release date: 2011-03-23, Last modification date: 2024-11-06)

Primary citation

Rueeger, H.,Rondeau, J.M.,McCarthy, C.,Mobitz, H.,Tintelnot-Blomley, M.,Neumann, U.,Desrayaud, S.
Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors.
Bioorg.Med.Chem.Lett., 21:1942-1947, 2011

PubMed Abstract: This Letter describes the de novo design of non-peptidic hydroxyethylamine (HEA) inhibitors of BACE-1 by elimination of P-gp contributing amide attachments. The predicted binding mode of the novel cyclic sulfone HEA core template was confirmed in a X-ray co-crystal structure. Inhibitors of sub-micromolar potency with an improved property profile over historic HEA inhibitors resulting in improved brain penetration are described.

PubMed: 21388807
DOI: 10.1016/j.bmcl.2011.02.038

Experimental method

X-RAY DIFFRACTION (2.4 Å)