6FSE

Mus musculus acetylcholinesterase in complex with 1-(4-(4-Ethylpiperazin-1-yl)piperidin-1-yl)-2-((4'-methoxy-[1,1'-biphenyl]-4-yl)oxy)ethanone dihydrochloride (15)

6FSE の概要

• エントリーDOI: 10.2210/pdb6fse/pdb
• 分子名称: Acetylcholinesterase, 1-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]-2-[4-(4-methoxyphenyl)phenoxy]ethanone, 2-(2-{2-[2-(2-METHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHANOL, ... (6 entities in total)
• 機能のキーワード: inhibitor, hydrolase, acetylcholinesterase, protein binding
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 121917.86

構造登録者

Knutsson, S.,Engdahl, C.,Kumari, R.,Kindahl, T.,Forsgren, N.,Lindgren, C.,Kitur, S.,Kamau, L.,Ekstrom, F.,Linusson, A. (登録日: 2018-02-19, 公開日: 2018-10-31, 最終更新日: 2024-11-13)

主引用文献

Knutsson, S.,Engdahl, C.,Kumari, R.,Forsgren, N.,Lindgren, C.,Kindahl, T.,Kitur, S.,Wachira, L.,Kamau, L.,Ekstrom, F.,Linusson, A.
Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency.
J.Med.Chem., 61:10545-10557, 2018

PubMed Abstract: Resistance development in insects significantly threatens the important benefits obtained by insecticide usage in vector control of disease-transmitting insects. Discovery of new chemical entities with insecticidal activity is highly desired in order to develop new insecticide candidates. Here, we present the design, synthesis, and biological evaluation of phenoxyacetamide-based inhibitors of the essential enzyme acetylcholinesterase 1 (AChE1). AChE1 is a validated insecticide target to control mosquito vectors of, e.g., malaria, dengue, and Zika virus infections. The inhibitors combine a mosquito versus human AChE selectivity with a high potency also for the resistance-conferring mutation G122S; two properties that have proven challenging to combine in a single compound. Structure-activity relationship analyses and molecular dynamics simulations of inhibitor-protein complexes have provided insights that elucidate the molecular basis for these properties. We also show that the inhibitors demonstrate in vivo insecticidal activity on disease-transmitting mosquitoes. Our findings support the concept of noncovalent, selective, and resistance-breaking inhibitors of AChE1 as a promising approach for future insecticide development.

PubMed: 30339371
DOI: 10.1021/acs.jmedchem.8b01060

実験手法

X-RAY DIFFRACTION (2.7 Å)