Interactions of monoamine oxidases with the antiepileptic drug zonisamide: specificity of inhibition and structure of the human monoamine oxidase B complex

Abstract

The binding of zonisamide to purified, recombinant monoamine oxidases (MAOs) has been investigated. It is a competitive inhibitor of human MAO B (K(i) = 3.1 ± 0.3 μM), of rat MAO B (K(i) = 2.9 ± 0.5 μM), and of zebrafish MAO (K(i) = 30.8 ± 5.3 μM). No inhibition is observed with purified human or rat MAO A. The 1.8 Å structure of the MAO B complex demonstrates that it binds within the substrate cavity.

Figure 1

Structure of Zonisamide (A). Panel B shows the Chem3D representation of the zonisamide structure with a Connolly surface included after energy minimization. Carbons are in gray, hydrogens in white, nitrogens in blue, oxygens in red, and sulfur in yellow.

Figure 2

Structural properties of Zonisamide binding to human MAO B. (A) Ribbon diagram of the overall structure of human MAO B in complex with zonisamide. The substrate-binding cavity is represented as semi-transparent surface. Zonisamide is shown in magenta, FAD in yellow, and the MAO B chain trace in blue. (B) Weighted 2Fo-Fc electron density of bound zonisamide in the active site of MAO B. The map was calculated before inclusion in the model of the inhibitor and, therefore, it is fully unbiased. Zonisamide carbons are in magenta, flavin carbons in yellow, oxygens in red, nitrogens in blue, sulphurs in light brown, and phosphorous in orange. This figure as well as Figures 3 and 4 were produced with PyMol (www.pymol.org).

Figure 3

Structure of zonisamide in the active site of MAO B. Zonisamide carbons are in magenta, flavin carbons in yellow, protein carbons in light blue, oxygens in red, nitrogens in blue, sulphurs in light brown, and phosphorous in orange. Water molecules apparent in the electron density are depicted as red spheres. H-bonds suggested from distance and geometry considerations are denoted by dashed lines.

Figure 4

Superposition of zonisamide-MAO B complex with those with (A) isatin (PDB 2BK5) and (B) safinamide (PDB 2V5Z). The colors of residues and atoms are as in Figure 3. The carbon skeletons of isatin and safinamide structures are depicted in gray.