7BO3

Human Butyrylcholinesterase in complex with N-(2-(1H-Indol-3-yl)ethyl)-2-cycloheptyl-N-methylethan-1-amine

7BO3 の概要

• エントリーDOI: 10.2210/pdb7bo3/pdb
• 分子名称: Cholinesterase, alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• 機能のキーワード: butyrylcholinesterase, complex, inhibitor, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 63053.79

構造登録者

Brazzolotto, X.,Meden, A.,Knez, D.,Nachon, F.,Gobec, S. (登録日: 2021-01-23, 公開日: 2022-03-02, 最終更新日: 2024-11-06)

主引用文献

Meden, A.,Knez, D.,Brazzolotto, X.,Nachon, F.,Dias, J.,Svete, J.,Stojan, J.,Groselj, U.,Gobec, S.
From tryptophan-based amides to tertiary amines: Optimization of a butyrylcholinesterase inhibitor series.
Eur.J.Med.Chem., 234:114248-114248, 2022

PubMed Abstract: Lead optimization of a series of tryptophan-based nanomolar butyrylcholinesterase (BChE) inhibitors led to tertiary amines as highly potent, achiral, sp-rich analogues with better synthetic accessibility and high selectivity over acetylcholinesterase (one to ten thousandfold). Taking it one step further, the introduction of a carbamate warhead on the well-explored reversible scaffold allowed conversion to pseudoirreversible inhibitors that bound covalently to BChE and prolonged the duration of inhibition (half-life of 14.8 h for compound 45a-carbamoylated enzyme). Additionally, N-hydroxyindole was discovered as a novel leaving group chemotype. The covalent mechanism of action was confirmed by time-dependency experiments, progress curve analysis, and indirectly by co-crystallization with the human recombinant enzyme. Two crystal structures of BChE-inhibitor complexes were solved and coupled with the supporting molecular dynamics simulations increased our understanding of the structure-activity relationship, while also providing the necessary structural information for future optimization of this series. Overall, this research demonstates the high versatility and potential of this series of BChE inhibitors.

PubMed: 35299116
DOI: 10.1016/j.ejmech.2022.114248

実験手法

X-RAY DIFFRACTION (2.2 Å)