4ZSM

BACE crystal structure with bicyclic aminothiazine fragment

Summary for 4ZSM

• Entry DOI: 10.2210/pdb4zsm/pdb
• Related: 4ZSP 4ZSQ 4ZSR
• Descriptor: Beta-secretase 1, (4aS,8aR)-4a,5,6,7,8,8a-hexahydro-4H-3,1-benzothiazin-2-amine, GLYCEROL, ... (4 entities in total)
• Functional Keywords: aspartyl, protease, beta-secretase, 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: 2
• Total formula weight: 98372.88

Authors

Timm, D.E. (deposition date: 2015-05-13, release date: 2015-06-10, Last modification date: 2024-10-09)

Primary citation

Winneroski, L.L.,Schiffler, M.A.,Erickson, J.A.,May, P.C.,Monk, S.A.,Timm, D.E.,Audia, J.E.,Beck, J.P.,Boggs, L.N.,Borders, A.R.,Boyer, R.D.,Brier, R.A.,Hudziak, K.J.,Klimkowski, V.J.,Garcia Losada, P.,Mathes, B.M.,Stout, S.L.,Watson, B.M.,Mergott, D.J.
Preparation and biological evaluation of conformationally constrained BACE1 inhibitors.
Bioorg.Med.Chem., 23:3260-3268, 2015

PubMed Abstract: The BACE1 enzyme is a key target for Alzheimer's disease. During our BACE1 research efforts, fragment screening revealed that bicyclic thiazine 3 had low millimolar activity against BACE1. Analysis of the co-crystal structure of 3 suggested that potency could be increased through extension toward the S3 pocket and through conformational constraint of the thiazine core. Pursuit of S3-binding groups produced low micromolar inhibitor 6, which informed the S3-design for constrained analogs 7 and 8, themselves prepared via independent, multi-step synthetic routes. Biological characterization of BACE inhibitors 6-8 is described.

PubMed: 26001341
DOI: 10.1016/j.bmc.2015.04.062

Experimental method

X-RAY DIFFRACTION (1.96 Å)