PDBsum entry 6ezh

Hydrolase

PDB id: 6ezh

Contents

Protein chains

532 a.a.

Ligands

NAG ×4

C6H ×2

Waters ×550

References listed in PDB file

Key reference

• Title: Novel multitarget-Directed ligands targeting acetylcholinesterase and σ₁ receptors as lead compounds for treatment of alzheimer'S disease: synthesis, Evaluation, And structural characterization of their complexes with acetylcholinesterase.
• Authors: J.Lalut, G.Santoni, D.Karila, C.Lecoutey, A.Davis, F.Nachon, I.Silman, J.Sussman, M.Weik, T.Maurice, P.Dallemagne, C.Rochais.
• Ref.: Eur J Med Chem, 2018, 162, 234-248. [DOI no: 10.1016/j.ejmech.2018.10.064]
• PubMed id: 30447434

Abstract

Pleiotropic intervention may be a requirement for effective limitation of the progression of multifactorial diseases such as Alzheimer's Disease. One approach to such intervention is to design a single chemical entity capable of acting on two or more targets of interest, which are accordingly known as Multi-Target Directed Ligands (MTDLs). We recently described donecopride, the first MTDL able to simultaneously inhibit acetylcholinesterase and act as an agonist of the 5-HT₄ receptor, which displays promising activities in vivo. Pharmacomodulation of donecopride allowed us to develop a novel series of indole derivatives possessing interesting in vitro activities toward AChE and the σ₁ receptor. The crystal structures of complexes of the most promising compounds with Torpedo californica AChE were solved in order to further understand their mode of inhibition.