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

• 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
• ISSN: 0031-9422; 1873-3700
• DOI: 10.1016/j.phytochem.2012.05.004

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► 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.