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

Abstract

Context: Paraoxonase 1 (PON1) is a crucial antioxidant enzyme involved in the hydrolysis oforganophosphates and the prevention of oxidative damage to lipoproteins. Objective: This studyaimed to purify PON1 using a newly synthesised hydrophobic interaction chromatography geland to investigate the inhibitory effects of selected emergency cardiac drugs on PON1 activitythrough in vitro and in silico approaches. Materials and methods: PON1 was purified using aSepharose-4B-L-tyrosine-6-aminochrysene hydrophobic interaction chromatography gel. Theinhibitory effects of deslanoside, digitoxin, esmolol, and adenosine were evaluated via kineticinhibition assays, molecular docking, molecular dynamics simulations, and MMPBSA calculations.Results: Among the tested compounds, esmolol exhibited the strongest inhibition of PON1activity (IC50 = 0.131 ± 0.071 μM, Ki = 0.044 ± 0.009 μM) via a competitive mechanism. Moleculardocking revealed strong binding affinity of esmolol to the PON1 active site, which was furthersupported by molecular dynamics simulations over 150 ns. Discussion and conclusion: Thefindings indicate a potential interaction between commonly used emergency cardiac drugs andPON1, highlighting the importance of evaluating off-target effects on critical metabolic enzymesin cardiovascular therapy