5TFT

Structure of cytochrome P450 2D6 (CYP2D6) BACE1 inhibitor complex

5TFT の概要

• エントリーDOI: 10.2210/pdb5tft/pdb
• 関連するPDBエントリー: 5T1U 5TFT
• 分子名称: Cytochrome P450 2D6, PROTOPORPHYRIN IX CONTAINING FE, ZINC ION, ... (5 entities in total)
• 機能のキーワード: cyp2d6, p450 2d6, cytochrome p450, monooxygenase, bace1, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 219232.82

構造登録者

Hsu, M.H.,Johnson, E.F. (登録日: 2016-09-26, 公開日: 2017-01-11, 最終更新日: 2023-10-04)

主引用文献

Butler, C.R.,Ogilvie, K.,Martinez-Alsina, L.,Barreiro, G.,Beck, E.M.,Nolan, C.E.,Atchison, K.,Benvenuti, E.,Buzon, L.,Doran, S.,Gonzales, C.,Helal, C.J.,Hou, X.,Hsu, M.H.,Johnson, E.F.,Lapham, K.,Lanyon, L.,Parris, K.,O'Neill, B.T.,Riddell, D.,Robshaw, A.,Vajdos, F.,Brodney, M.A.
Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality.
J. Med. Chem., 60:386-402, 2017

PubMed Abstract: A growing subset of β-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) utilizes an anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability and provides a potential metabolic site leading to the formation of an aniline, a structural motif of prospective safety concern. We report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety. Optimization of this series identified analogues with an excellent balance of ADME properties and potency; however, potential drug-drug interactions (DDI) were predicted based on CYP 2D6 affinities. Generation and analysis of key BACE1 and CYP 2D6 crystal structures identified strategies to obviate the DDI liability, leading to compound 16, which exhibits robust in vivo efficacy as a BACE1 inhibitor.

PubMed: 27997172
DOI: 10.1021/acs.jmedchem.6b01451

実験手法

X-RAY DIFFRACTION (2.71 Å)