In vitro activation of paraoxonase 1 by steroids: An experimental, molecular docking, and molecular modelling study

Abstract

Paraoxonase 1 (PON1) is an antioxidant enzyme that prevents lipid oxidation by hydrolysing lipid peroxides in the oxidised low-density lipoprotein (LDL) structure, bound to high-density lipoprotein (HDL) in serum, and exhibits esterase and lactonase activity. In this work, the hPON1 enzyme was purified from human serum using a hydrophobic gel with Sepharose 4B-L-tyrosine-naphthylamine, and the affinity of some steroid derivatives previously isolated from fungal steroid biotransformations was examined on the pure hPON1 enzyme. The results indicate that all these derivaties activate the hPON1 enzyme to a different extent. Additionally, the binding potential of the most active five steroid derivatives to the PON1 enzyme to form a stable complex was explored through molecular docking and molecular dynamics (MD) simulation. The compounds with the highest potency in the enzymatic assay, S-8 and S-20, had the highest binding potential to the enzyme. The stability of the complexes formed by the two compounds was assessed and compared to the stability of the unbound enzyme structure. The enzyme-compound complexes generally had similar stability to the unbound enzyme structure. Together with this, the MD simulation revealed that compound S-8 would remain inside the enzyme's binding site during the simulation period, unlike compound S-20. This situation varies according to the respective derivatives' functional groups and hydrophobic characteristics.