6BFD

BACE crystal structure with hydroxy pyrrolidine inhibitor

6BFD の概要

• エントリーDOI: 10.2210/pdb6bfd/pdb
• 分子名称: Beta-secretase 1, 2-{[(2S)-butan-2-yl]amino}-N-{(1R,2S)-1-hydroxy-3-phenyl-1-[(2R)-pyrrolidin-2-yl]propan-2-yl}-6-(methylsulfonyl)pyridine-4-carboxamide, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: bace1, beta-secretase, inhibitor, protease, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase 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: 2
• 化学式量合計: 99257.84

構造登録者

Timm, D.E. (登録日: 2017-10-26, 公開日: 2017-11-15, 最終更新日: 2024-11-20)

主引用文献

Bueno, A.B.,Agejas, J.,Broughton, H.,Dally, R.,Durham, T.B.,Espinosa, J.F.,Gonzalez, R.,Hahn, P.J.,Marcos, A.,Rodriguez, R.,Sanz, G.,Soriano, J.F.,Timm, D.,Vidal, P.,Yang, H.C.,McCarthy, J.R.
Optimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational Preferences.
J. Med. Chem., 60:9807-9820, 2017

PubMed Abstract: NMR conformational analysis of a hydroxyethylamine peptide isostere developed as an aspartic protease inhibitor shows that it is a flexible architecture. Cyclization to form pyrrolidines, piperidines, or morpholines results in a preorganization of the whole system in solution. The resulting conformation is similar to the conformation of the inhibitor in the active site of BACE-1. This entropic gain results in increased affinity for the enzyme when compared with the acyclic system. For morpholines 27 and 29, the combination of steric and electronic factors is exploited to orient substituents toward S1, S1', and S2' pockets both in the solution and in the bound states. These highly preorganized molecules proved to be the most potent compounds of the series. Additionally, the morpholines, unlike the pyrrolidine and piperidine analogues, have been found to be brain penetrant BACE-1 inhibitors.

PubMed: 29088532
DOI: 10.1021/acs.jmedchem.7b01304

実験手法

X-RAY DIFFRACTION (1.62 Å)