4ZPG

BACE1 in complex with 8-benzyl-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one

4ZPG の概要

• エントリーDOI: 10.2210/pdb4zpg/pdb
• 分子名称: Beta-secretase 1, (5R,7S)-8-benzyl-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one (3 entities in total)
• 機能のキーワード: alzheimer disease, amyloid precursor protein secretases, amyloid beta-peptides, aspartic acid endopeptidases, binding sites, drug design, molecular, protease inhibitors, structure-activity relationship, 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: 45571.33

構造登録者

Orth, P. (登録日: 2015-05-07, 公開日: 2015-08-05, 最終更新日: 2024-10-23)

主引用文献

Egbertson, M.,McGaughey, G.B.,Pitzenberger, S.M.,Stauffer, S.R.,Coburn, C.A.,Stachel, S.J.,Yang, W.,Barrow, J.C.,Neilson, L.A.,McWherter, M.,Perlow, D.,Fahr, B.,Munshi, S.,Allison, T.J.,Holloway, K.,Selnick, H.G.,Yang, Z.,Swestock, J.,Simon, A.J.,Sankaranarayanan, S.,Colussi, D.,Tugusheva, K.,Lai, M.T.,Pietrak, B.,Haugabook, S.,Jin, L.,Chen, I.W.,Holahan, M.,Stranieri-Michener, M.,Cook, J.J.,Vacca, J.,Graham, S.L.
Methyl-substitution of an iminohydantoin spiropiperidine beta-secretase (BACE-1) inhibitor has a profound effect on its potency.
Bioorg.Med.Chem.Lett., 25:4812-4819, 2015

PubMed Abstract: The IC50 of a beta-secretase (BACE-1) lead compound was improved ∼200-fold from 11 μM to 55 nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.

PubMed: 26195137
DOI: 10.1016/j.bmcl.2015.06.082

実験手法

X-RAY DIFFRACTION (2 Å)