4D85

Crystal Structure of Human Beta Secretase in Complex with NVP-BVI151

4D85 の概要

• エントリーDOI: 10.2210/pdb4d85/pdb
• 関連するPDBエントリー: 3VEU 3VF3 3VG1 4D83 4D88 4D89 4D8C
• 分子名称: Beta-secretase 1, (3R,4S,5S)-3-[(3-tert-butylbenzyl)amino]-5-[(4,4,7'-trifluoro-1',2'-dihydrospiro[cyclohexane-1,3'-indol]-5'-yl)methyl]tetrahydro-2H-thiopyran-4-ol 1,1-dioxide, IODIDE ION, ... (4 entities in total)
• 機能のキーワード: beta-secretase, memapsin2, bace1, aspartic proteinase, alzheimer's disease, enzyme inhibitor complex, structure-based drug design, 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: 1
• 化学式量合計: 46126.56

構造登録者

Rondeau, J.M.,Bourgier, E. (登録日: 2012-01-10, 公開日: 2012-11-21, 最終更新日: 2024-10-16)

主引用文献

Rueeger, H.,Lueoend, R.,Rogel, O.,Rondeau, J.M.,Mobitz, H.,Machauer, R.,Jacobson, L.,Staufenbiel, M.,Desrayaud, S.,Neumann, U.
Discovery of cyclic sulfone hydroxyethylamines as potent and selective beta-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid beta-peptides
J.Med.Chem., 55:3364-3386, 2012

PubMed Abstract: Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure-activity relationship development were supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with central nervous system drugs led to inhibitors with improved blood-brain barrier permeability. Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC(50) values of 2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APP51/16 transgenic mice at oral doses of 180 μmol/kg demonstrated significant reduction of brain Aβ levels.

PubMed: 22380629
DOI: 10.1021/jm300069y

実験手法

X-RAY DIFFRACTION (2.65 Å)