2ZE1

X-ray structure of Bace-1 in complex with compound 6g

Summary for 2ZE1

• Entry DOI: 10.2210/pdb2ze1/pdb
• Related: 2QU2 2QU3 2ZDZ
• Descriptor: Beta-secretase 1, 3-bromo-N-[4-[1-(2-carbamimidamido-2-oxo-ethyl)-5-phenyl-pyrrol-2-yl]phenyl]benzamide (3 entities in total)
• Functional Keywords: bace, aspartyl protease, acylguanidine inhibitor, alternative splicing, glycoprotein, hydrolase, membrane, transmembrane, zymogen
• Biological source: Homo sapiens (Human)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 1
• Total formula weight: 46957.37

Authors

Chopra, R.,Olland, A. (deposition date: 2007-12-05, release date: 2008-12-09, Last modification date: 2024-10-23)

Primary citation

Cole, D.C.,Stock, J.R.,Chopra, R.,Cowling, R.,Ellingboe, J.W.,Fan, K.Y.,Harrison, B.L.,Hu, Y.,Jacobsen, S.,Jennings, L.D.,Jin, G.,Lohse, P.A.,Malamas, M.S.,Manas, E.S.,Moore, W.J.,O'Donnell, M.M.,Olland, A.M.,Robichaud, A.J.,Svenson, K.,Wu, J.,Wagner, E.,Bard, J.
Acylguanidine inhibitors of beta-secretase: optimization of the pyrrole ring substituents extending into the S1 and S3 substrate binding pockets.
Bioorg.Med.Chem.Lett., 18:1063-1066, 2008

PubMed Abstract: Proteolytic cleavage of amyloid precursor protein by beta-secretase (BACE-1) and gamma-secretase leads to formation of beta-amyloid (A beta) a key component of amyloid plaques, which are considered the hallmark of Alzheimer's disease. Small molecule inhibitors of BACE-1 may reduce levels of A beta and thus have therapeutic potential for treating Alzheimer's disease. We recently reported the identification of a novel small molecule BACE-1 inhibitor N-[2-(2,5-diphenyl-pyrrol-1-yl)-acetyl]guanidine (3.a.1). We report here the initial hit-to-lead optimization of this hit and the SAR around the aryl groups occupying the S(1) and S(2') pockets leading to submicromolar BACE-1 inhibitors.

PubMed: 18162398
DOI: 10.1016/j.bmcl.2007.12.010

Experimental method

X-RAY DIFFRACTION (2.2 Å)