6EJ2

BACE1 compound 28

6EJ2 の概要

• エントリーDOI: 10.2210/pdb6ej2/pdb
• 分子名称: Beta-secretase 1, compound 28 (3 entities in total)
• 機能のキーワード: bace1, protease, alzheimer, peptide binding protein
• 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: 56193.96

構造登録者

Johansson, P. (登録日: 2017-09-20, 公開日: 2018-04-18, 最終更新日: 2024-11-06)

主引用文献

Johansson, P.,Kaspersson, K.,Gurrell, I.K.,Back, E.,Eketjall, S.,Scott, C.W.,Cebers, G.,Thorne, P.,McKenzie, M.J.,Beaton, H.,Davey, P.,Kolmodin, K.,Holenz, J.,Duggan, M.E.,Budd Haeberlein, S.,Burli, R.W.
Toward beta-Secretase-1 Inhibitors with Improved Isoform Selectivity.
J. Med. Chem., 61:3491-3502, 2018

PubMed Abstract: BACE1 is responsible for the first step in APP proteolysis, leading to toxic Aβ production, and has been indicated to play a key role in the pathogenesis of Alzheimer's disease. The related isoform BACE2 is thought to be involved in processing of the pigment cell-specific melanocyte protein. To avoid potential effects on pigmentation, we investigated the feasibility for developing isoform-selective BACE1 inhibitors. Cocrystal structures of 47 compounds were analyzed and clustered according to their selectivity profiles. Selective BACE1 inhibitors were found to exhibit two distinct conformational features proximal to the flap and the S3 subpocket. Several new molecules were designed and tested to make use of this observation. The combination of a pyrimidinyl C-ring and a methylcyclohexyl element resulted in lead molecule 28, which exhibited ∼50-fold selectivity. Compared to a nonselective BACE1/2 inhibitor, 28 showed significantly less inhibition of PMEL processing in human melanocytes, indicating good functional selectivity of this inhibitor class.

PubMed: 29617572
DOI: 10.1021/acs.jmedchem.7b01716

実験手法

X-RAY DIFFRACTION (1.46 Å)