5LKR

Human Butyrylcholinesterase complexed with N-Propargyliperidines

Summary for 5LKR

• Entry DOI: 10.2210/pdb5lkr/pdb
• Descriptor: Cholinesterase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• Functional Keywords: alzheimer disease ad butyrylcholinesterase n-propargyliperidines, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 136625.29

Authors

Coquelle, N.,Knez, D.,Colletier, J.P.,Gobec, S. (deposition date: 2016-07-23, release date: 2016-12-14, Last modification date: 2024-10-16)

Primary citation

Kosak, U.,Knez, D.,Coquelle, N.,Brus, B.,Pislar, A.,Nachon, F.,Brazzolotto, X.,Kos, J.,Colletier, J.P.,Gobec, S.
N-Propargylpiperidines with naphthalene-2-carboxamide or naphthalene-2-sulfonamide moieties: Potential multifunctional anti-Alzheimer's agents.
Bioorg. Med. Chem., 25:633-645, 2017

PubMed Abstract: In the brains of patients with Alzheimer's disease, the enzymatic activities of butyrylcholinesterase (BChE) and monoamine oxidase B (MAO-B) are increased. While BChE is a viable therapeutic target for alleviation of symptoms caused by cholinergic hypofunction, MAO-B is a potential therapeutic target for prevention of neurodegeneration in Alzheimer's disease. Starting with piperidine-based selective human (h)BChE inhibitors and propargylamine-based MAO inhibitors, we have designed, synthesized and biochemically evaluated a series of N-propargylpiperidines. All of these compounds inhibited hBChE with good selectivity over the related enzyme, acetylcholinesterase, and crossed the blood-brain barrier in a parallel artificial membrane permeation assay. The crystal structure of one of the inhibitors (compound 3) in complex with hBChE revealed its binding mode. Three compounds (4, 5, 6) showed concomitant inhibition of MAO-B. Additionally, the most potent hBChE inhibitor 7 and dual BChE and MAO-B inhibitor 6 were non-cytotoxic and protected neuronal SH-SY5Y cells from toxic amyloid β-peptide species.

PubMed: 27908752
DOI: 10.1016/j.bmc.2016.11.032

Experimental method

X-RAY DIFFRACTION (2.52 Å)