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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Inhibition of monoamine oxidase by (E)-styrylisatin analogues
Bioorganic and Medicinal Chemistry Letters, Volume 19, No. 9, Year 2009
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Description
Previous studies have shown that (E)-8-(3-chlorostyryl)caffeine (CSC) is a specific reversible inhibitor of human monoamine oxidase B (MAO-B) and does not bind to human MAO-A. Since the small molecule isatin is a natural reversible inhibitor of both MAO-B and MAO-A, (E)-5-styrylisatin and (E)-6-styrylisatin analogues were synthesized in an attempt to identify inhibitors with enhanced potencies and specificities for MAO-B. The (E)-styrylisatin analogues were found to exhibit higher binding affinities than isatin with the MAO preparations tested. The (E)-5-styrylisatin analogues bound more tightly than the (E)-6 analogue although the latter exhibits the highest MAO-B selectivity. Molecular docking studies with MAO-B indicate that the increased binding affinity exhibited by the (E)-styrylisatin analogues, in comparison to isatin, is best explained by the ability of the styrylisatins to bridge both the entrance cavity and the substrate cavity of the enzyme. Experimental support for this model is shown by the weaker binding of the analogues to the Ile199Ala mutant of human MAO-B. The lower selectivity of the (E)-styrylisatin analogues between MAO-A and MAO-B, in contrast to CSC, is best explained by the differing relative geometries of the aromatic rings for these two classes of inhibitors. © 2009 Elsevier Ltd. All rights reserved.
Authors & Co-Authors
van der Walt, Elizna M.
South Africa, Potchefstroom
North-west University
Milczek, Erika M.
United States, Atlanta
Emory University
Malan, Sarel F.
South Africa, Potchefstroom
North-west University
Edmondson, Dale Edward
United States, Atlanta
Emory University
Castagnoli, Neal E.
United States, Blacksburg
The Edward Via College of Osteopathic Medicine
Bergh, Jacobus J.
South Africa, Potchefstroom
North-west University
Petzer, Jacobus P.
South Africa, Potchefstroom
North-west University
Statistics
Citations: 38
Authors: 7
Affiliations: 3
Identifiers
Doi:
10.1016/j.bmcl.2009.03.030
ISSN:
0960894X