Flavonoids from Sideritis Species: Human Monoamine Oxidase (hMAO) Inhibitory Activities, Molecular Docking Studies and Crystal Structure of Xanthomicrol

Abstract

The inhibitory effects of flavonoids on monoamine oxidases (MAOs) have attracted great interest since alterations in monoaminergic transmission are reported to be related to neurodegenerative diseases such as Parkinson's and Alzheimer's diseases and psychiatric disorders such as depression and anxiety, thus MAOs may be considered as targets for the treatment of these multi-factorial diseases. In the present study, four Sideritis flavonoids, xanthomicrol (1), isoscutellarein 7-O-[6'''-O-acetyl-β-D-allopyranosyl-(1→2)]-β-D-glucopyranoside (2), isoscutellarein 7-O-[6'''-O-acetyl-β-D-allopyranosyl-(1→2)]-6''-O-acetyl-β-D-glucopyranoside (3) and salvigenin (4) were docked computationally into the active site of the human monoamine oxidase isoforms (hMAO-A and hMAO-B) and were also investigated for their hMAO inhibitory potencies using recombinant hMAO isoenzymes. The flavonoids inhibited hMAO-A selectively and reversibly in a competitive mode. Salvigenin (4) was found to be the most potent hMAO-A inhibitor, while xanthomicrol (1) appeared as the most selective hMAO-A inhibitor. The computationally obtained results were in good agreement with the corresponding experimental values. In addition, the x-ray structure of xanthomicrol (1) has been shown. The current work warrants further preclinical studies to assess the potential of xanthomicrol (1) and salvigenin (4) as new selective and reversible hMAO-A inhibitors for the treatment of depression and anxiety.

Figure 1

Structures of the four studied flavonoids: xanthomicrol (1), isoscutellarein 7-O-[6'''-O-acetyl-β-d-allopyranosyl-(1→2)]-β-d-glucopyranoside (2), isoscutellarein 7-O-[6'''-O-acetyl-β-d-allopyranosyl-(1→2)]-6''-O-acetyl-β-d-gluco-pyranoside (3) and salvigenin (4).

Figure 2

(A) Lineweaver–Burk plot of the competitive inhibition of hMAO-A by compound xanthomicrol (1) (B) Replot of data from the Lineweaver-Burk plot. The K_i value calculated from replots of the slopes of the Lineweaver-Burk plots versus inhibitor concentrations was found as 0.76 μM.

Figure 3

(A) Lineweaver-Burk plot of the competitive inhibition of hMAO-A by compound salvigenin (4); (B) Replot of data from the Lineweaver–Burk plot. The K_i value calculated from replots of the slopes of the Lineweaver–Burk plots versus inhibitor concentrations was found as 0.54 μM.

Figure 4

The 3 and 2 dimensional orientations of xanthomicrol (1) in the active site of hMAO-A. (A) 3D: Amino acid side chains are shown as sticks, the inhibitor is shown as a ball and stick (green), and the cofactor FAD is depicted as a yellow stick; (B) 2D: Purple color shows electrostatic and green color shows van der Waals atractions.

Figure 5

The 3 and 2 dimensional orientations of salvigenin (4) in the active site of hMAO-A. (A) 3D: Amino acid side chains are shown as sticks, the inhibitor is shown as a ball and stick (green), and the cofactor FAD is depicted as a yellow stick; (B) 2D: Purple color shows electrostatic and green color shows van der Waals atractions.

Figure 6

The 3 and 2 dimensional orientations of xanthomicrol (1) in the active site of hMAO-B. (A) 3D: Amino acid side chains are shown as sticks, the inhibitor is shown as a ball and stick (green), and the cofactor FAD is depicted as a yellow stick; (B) 2D: Purple color shows electrostatic and green color shows van der Waals atractions.

Figure 7

The 3 and 2 dimensional orientations of salvigenin (4) in the active site of hMAO-B. (A) 3D: Amino acid side chains are shown as sticks, the inhibitor is shown as a ball and stick (green), and the cofactor FAD is depicted as a yellow stick; (B) 2D: Purple color shows electrostatic and green color shows van der Waals atractions.

Figure 8

Crystal structure of xanthomicrol (4) showing two molecules in asymmetric unit and the crystal packing and alignment.

Figure 9

Hydrogen bond interactions of crystal.