Inhibitory effects and molecular interaction analysis of emergency cardiac drugs on human serum paraoxonase 1: an integrated in vitro and in silico approach.

Context: Paraoxonase 1 (PON1) is a crucial antioxidant enzyme involved in the hydrolysis of organophosphates and the prevention of oxidative damage to lipoproteins.

Objective

This study aimed to purify PON1 using a newly synthesised hydrophobic interaction chromatography gel and to investigate the inhibitory effects of selected emergency cardiac drugs on PON1 activity through in vitro and in silico approaches. Materials and methods: PON1 was purified using a Sepharose-4B-L-tyrosine-6-aminochrysene hydrophobic interaction chromatography gel. The inhibitory effects of deslanoside, digitoxin, esmolol, and adenosine were evaluated via kinetic inhibition assays, molecular docking, molecular dynamics simulations, and MMPBSA calculations.

Results

Among the tested compounds, esmolol exhibited the strongest inhibition of PON1 activity (IC50 = 0.131 ± 0.071 μM, Ki = 0.044 ± 0.009 μM) via a competitive mechanism. Molecular docking revealed strong binding affinity of esmolol to the PON1 active site, which was further supported by molecular dynamics simulations over 150 ns. Discussion and conclusion: The findings indicate a potential interaction between commonly used emergency cardiac drugs and PON1, highlighting the importance of evaluating off-target effects on critical metabolic enzymes in cardiovascular therapy.