4I0Z

Structure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates

Summary for 4I0Z

• Entry DOI: 10.2210/pdb4i0z/pdb
• Related: 4HZI 4I0D 4I0E 4I0F 4I0G 4I10 4I12 4I1C
• Descriptor: 2-{(1S)-1-[(6-CHLORO-3,3-DIMETHYL-3,4-DIHYDROISOQUINOLIN-1-YL)AMINO]-2-PHENYLETHYL}-4-OXO-1,4-DIHYDROPYRIMIDINE-5-CARBONITRILE, 2-{(1S)-1-[(6-chloro-3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)amino]-2-phenylethyl}-4-oxo-1,4-dihydropyrimidine-5-carbonitrile, ZINC ION, ... (4 entities in total)
• Functional Keywords: aspartic protease, 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: 1
• Total formula weight: 46138.67

Authors

Lougheed, J.C.,Brecht, E.,Yao, N.H. (deposition date: 2012-11-19, release date: 2013-03-06, Last modification date: 2024-10-16)

Primary citation

Bowers, S.,Xu, Y.Z.,Yuan, S.,Probst, G.D.,Hom, R.K.,Chan, W.,Konradi, A.W.,Sham, H.L.,Zhu, Y.L.,Beroza, P.,Pan, H.,Brecht, E.,Yao, N.,Lougheed, J.,Tam, D.,Ren, Z.,Ruslim, L.,Bova, M.P.,Artis, D.R.
Structure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates.
Bioorg.Med.Chem.Lett., 23:2181-2186, 2013

PubMed Abstract: The structure-activity relationship of a series of dihydroisoquinoline BACE-1 inhibitors is described. Application of structure-based design to screening hit 1 yielded sub-micromolar inhibitors. Replacement of the carboxylic acid of 1 was guided by X-ray crystallography, which allowed the replacement of a key water-mediated hydrogen bond. This work culminated in compounds such as 31, which possess good BACE-1 potency, excellent permeability and a low P-gp efflux ratio.

PubMed: 23465612
DOI: 10.1016/j.bmcl.2013.01.103

Experimental method

X-RAY DIFFRACTION (1.8 Å)