Structural insights into cholinesterases inhibition by harmane β-carbolinium derivatives: a kinetics-molecular modeling approach.
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.
Departamento de Química, Instituto de Ciências Exatas, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ, Brazil.
Juliana M
JM
Torres
Aline F
AF
Lira
Daniel R
DR
Silva
Lucas M
LM
Guzzo
Carlos M R
CM
Sant'Anna
Arthur E
AE
Kümmerle
Victor M
VM
Rumjanek
D000109:Acetylcholine / Q000737:chemistry; D002243:Carbolines / Q000737:chemistry*; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000737:chemistry*; D002802:Cholinesterases / Q000737:chemistry*; D004789:Enzyme Activation; D006247:Harmine / Q000031:analogs & derivatives* / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D025941:Protein Interaction Mapping; D019666:Rubiaceae / Q000737:chemistry; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D002243:Carbolines; D002800:Cholinesterase Inhibitors; D006247:Harmine; C005010:harman; D002802:Cholinesterases; D000109:Acetylcholine