Structural insights into cholinesterases inhibition by harmane β-carbolinium derivatives: A kinetics – molecular modeling approach

Structural insights into cholinesterases inhibition by harmane β-carbolinium derivatives: A kinetics – molecular modeling approach

[Display omitted] ► The inhibition kinetics of cholinesterases by β-carbolinium salts were determined. ► A molecular modeling study of its enzyme–ligand interactions was carried out. ► The positive charge does not mimic the natural substrate. ► Selectivity was observed between enzymes of up to 20 ti...

Full description

Saved in:
Bibliographic Details
Published in:Phytochemistry (Oxford) Vol. 81; pp. 24 - 30
Main Authors: Torres, Juliana M., Lira, Aline F., Silva, Daniel R., Guzzo, Lucas M., Sant’Anna, Carlos M.R., Kümmerle, Arthur E., Rumjanek, Victor M.
Format: Journal Article
Language:English
Published: England Elsevier Ltd 01-09-2012
Subjects:
acetylcholine
Acetylcholine - chemistry
Carbolines - chemistry
Catalytic Domain
choline
cholinesterase
Cholinesterase Inhibitors - chemistry
Cholinesterase kinetics
Cholinesterases - chemistry
Enzyme Activation
enzyme inhibitors
Harmane
Harmine - analogs & derivatives
Harmine - chemistry
indole alkaloids
Inhibitory Concentration 50
Kinetics
Models, Chemical
Molecular Dynamics Simulation
molecular models
Protein Interaction Mapping
Rubiaceae - chemistry
salts
Static Electricity
Structure-Activity Relationship
Substrate Specificity
β-Carbolines
Harmane
β-Carbolines
Cholinesterase kinetics
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:[Display omitted] ► The inhibition kinetics of cholinesterases by β-carbolinium salts were determined. ► A molecular modeling study of its enzyme–ligand interactions was carried out. ► The positive charge does not mimic the natural substrate. ► Selectivity was observed between enzymes of up to 20 times for the salts. The natural indole alkaloids, the β-carbolines, are often associated with cholinesterase inhibition, especially their quaternary salts, which frequently have higher activity than the free bases. Due to lack of information explaining this fact in the literature, the cholinesterase inhibition by the natural product harmane and its two β-carbolinium synthetic derivative salts (N-methyl and N-ethyl) was explored, together with a combination of kinetics and a molecular modeling approach. The results, mainly for the β-carbolinium salts, demonstrated a noncompetitive inhibition profile, ruling out previous findings which associated cholinesterase inhibition by β-carbolinium salts to a possible mimicking of the choline moiety of the natural substrate, acetylcholine. Molecular modeling studies corroborate this kind of inhibition through analyses of inhibitor/enzyme and inhibitor/substrate/enzyme complexes of both enzymes.
Bibliography:http://dx.doi.org/10.1016/j.phytochem.2012.05.004
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0031-9422
1873-3700
DOI:10.1016/j.phytochem.2012.05.004