Gadolinium-based contrast agents: in vitro paraoxonase 1 inhibition, in silico studies

Abstract

Medications show their biological effects by interaction with enzymes, which have been known to play an essential role in the pathogenesis of many diseases. Inhibition or induction of drug metabolizing enzymes has an essential place in the drug design for many kinds of diseases including cardiovascular, neurological, metabolic, and cancer. The main goal of the current study is to contribute to this growing drug design field by observing PON1–drug interactions. In recent years, the safety of gadolinium-based contrast agents (GBCAs) used in magnetic resonance imaging (MRI) has discussed. In the present study, paraoxonase 1 (PON1) enzyme was purified from human serum by simple chromatographic methods with 4095.24 EU mg⁻¹ protein specific activity. The inhibitory activities of gadoteric acid, gadopentetic acid, gadoxetate disodium, and gadodiamide were investigated on PON1 activity of the enzyme. IC₅₀ values were found in the range of 51.28 ± 0.14 to 285.80 ± 0.96 mM. K_i constants were found as 67.95 ± 0.60 mM, 104.97 ± 0.96 mM, 202.33 ± 1.75 mM, and 299.43 ± 2.64 mM for gadoteric acid, gadopentetic acid, gadoxetate disodium, and gadodiamide, respectively. While the inhibition types are determined as competitive of gadoxetate disodium and gadodiamide by the Lineweaver–Burk curves, it was noncompetitive for other compounds. In addition, the molecular docking analyses of gadoxetate disodium and gadodiamide were carried out to understand the binding interactions on the active site of the PON1 enzyme. The structure–activity relationship (SAR) of the drugs was established on the basis of different substituents and their positions in the compounds.

Keywords:

• Paraoxonase
• HDL
• chromatography
• inhibition
• gadolinium-based contrast agents
• molecular docking

Acknowledgements

The authors are thankful to Samet Karataş and Muhammed Kerem Türkeş for his helpful suggestions during the preparation of the manuscript.

Disclosure statement

The authors report no conflict of interest.

Additional information

Funding

This work was supported by the Research Fund of Anadolu University under Grant numbers 1610S681 and 1610C681; and the Research Fund Erzincan Binali Yıldırım University under Grant number FBA-2017-501. The authors are grateful to Anadolu University and Erzincan Binali Yıldırım University for financial support.