Polyphenols from Citrus Tacle® Extract Endowed with HMGCR Inhibitory Activity: An Antihypercholesterolemia Natural Remedy

Abstract

Tacle^® is a citrus fruit obtained from the crossbreeding of Clementine and Tarocco cultivars. This fruit retains a promising nutraceutical potential most likely due to a high content in polyphenols, among which the main constituents are the two glycosides naringin and hesperidin. Herein, we evaluated, through an in vitro assay, the capability of Tacle extracts to inhibit the hydroxymethylglutaryl-CoA reductase enzyme, which plays a key role in cholesterol biosynthesis. The results obtained spurred us to investigate whether the anti-enzymatic activity observed may be due to a direct interaction of aglycones naringenin and hesperetin with the enzyme catalytic site. Molecular docking simulations indicated that these two compounds are able to anchor to the protein with binding modes and affinities similar to those found for statins, which represent mainstream medications against hypercholesterolemia. The overall results showed an interesting nutraceutical potential of Tacle, suggesting that its extract could be used for dietary supplementation in the treatment of moderate hypercholesterolemia.

Keywords: anti-enzymatic assays; flavanones; molecular docking.

Figure 1

(A) Visualization of the tetrameric assembly of the catalytic domains of HMGCR; (B) Schematic representation of the arrangement of the chains (A, B, C, and D) and location of the active sites (1, 2, 3, and 4).

Figure 2

(A) Chemical structure of naringenin (R = H, R’ = OH) and hesperetin (R = OH, R’ = OMe); (B–F) Ligand-binding pocket of the active site of HMGCR; ribbons representing protein structural element are shown. The key residues are also indicated. (B) Superimposed binding modes of all the six crystallographic statins: mevastatin (pink), cerivastatin (magenta), simvastatin (dark green), rosuvastatin (purple), fluvastatin (blue), atorvastatin (orange); (C) binding mode of mevastatin; (D) superimposed binding modes of the two flavonoid ligands: naringenin (yellow) and hesperetin (light green); specific binding mode of naringenin (E), hesperetin (F).