4I11

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

4I11 の概要

• エントリーDOI: 10.2210/pdb4i11/pdb
• 関連するPDBエントリー: 4HZT 4I0Z 4I10
• 分子名称: Beta-secretase 1, ZINC ION, N-(3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)-L-phenylalanine, ... (4 entities in total)
• 機能のキーワード: bace-1, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P56817
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 45963.75

構造登録者

Bowers, B.,Xu, Y.,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.,Artis, D.R.,Tam, D.,Bova, M. (登録日: 2012-11-19, 公開日: 2013-03-06, 最終更新日: 2024-11-27)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.89 Å)