6SAM

Structure of human butyrylcholinesterase in complex with 1-(2,3-dihydro-1H-inden2-yl)piperidin-3-yl N-phenyl carbamate

Summary for 6SAM

• Entry DOI: 10.2210/pdb6sam/pdb
• Descriptor: Cholinesterase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: butyrylcholinesterase, inhibitor, complex, carbamate, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 63026.79

Authors

Brazzolotto, X.,Kosak, U.,Strasek, N.,Knez, D.,Gobec, S.,Nachon, F. (deposition date: 2019-07-17, release date: 2020-04-29, Last modification date: 2024-11-20)

Primary citation

Kosak, U.,Strasek, N.,Knez, D.,Jukic, M.,Zakelj, S.,Zahirovic, A.,Pislar, A.,Brazzolotto, X.,Nachon, F.,Kos, J.,Gobec, S.
N-alkylpiperidine carbamates as potential anti-Alzheimer's agents.
Eur.J.Med.Chem., 197:112282-112282, 2020

PubMed Abstract: Compounds capable of interacting with single or multiple targets involved in Alzheimer's disease (AD) pathogenesis are potential anti-Alzheimer's agents. In our aim to develop new anti-Alzheimer's agents, a series of 36 new N-alkylpiperidine carbamates was designed, synthesized and evaluated for the inhibition of cholinesterases [acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)] and monoamine oxidases [monoamine oxidase A (MAO-A and monoamine oxidase B (MAO-B)]. Four compounds are very promising: multiple AChE (IC = 7.31 μM), BChE (IC = 0.56 μM) and MAO-B (IC = 26.1 μM) inhibitor 10, dual AChE (IC = 2.25 μM) and BChE (IC = 0.81 μM) inhibitor 22, selective BChE (IC = 0.06 μM) inhibitor 13, and selective MAO-B (IC = 0.18 μM) inhibitor 16. Results of enzyme kinetics experiments showed that despite the carbamate group in the structure, compounds 10, 13, and 22 are reversible and non-time-dependent inhibitors of AChE and/or BChE. The resolved crystal structure of the complex of BChE with compound 13 confirmed the non-covalent mechanism of inhibition. Additionally, N-propargylpiperidine 16 is an irreversible and time-dependent inhibitor of MAO-B, while N-benzylpiperidine 10 is reversible. Additionally, compounds 10, 13, 16, and 22 should be able to cross the blood-brain barrier and are not cytotoxic to human neuronal-like SH-SY5Y and liver HepG2 cells. Finally, compounds 10 and 16 also prevent amyloid β (Aβ)-induced neuronal cell death. The neuroprotective effects of compound 16 could be the result of its Aβ anti-aggregation effects.

PubMed: 32380361
DOI: 10.1016/j.ejmech.2020.112282

Experimental method

X-RAY DIFFRACTION (2.5 Å)