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Inhibition of Human Serum Paraoxonase-I with Antimycotic Drugs: In Vitro and In Silico Studies

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Abstract

Drugs show their pharmacological effects by inhibiting or activating enzymes. Therefore, enzyme inhibitors have an essential place in the drug design for numerous different sorts of diseases, i.e., cardiovascular, cancer, metabolic, and neurological. The purpose of the current study was to contribute to the growing drug discovery and development area by analyzing functions and drug interactions of paraoxonase-I. For this purpose, the PON1 enzyme was purified from fresh human serum using simple, rapid, and different chromatographic techniques. Then, it was tested for the inhibitory effects of some antimycotic drugs on the PON1. Also, molecular docking analyses of each drug were carried out to determine the binding interactions on the active site of the PON1 enzyme. It was identified that the purified enzyme had the specific activity of 3880.83 EU/mg proteins and the molecular weight of 43 kDa by SDS-PAGE. IC50 values for PON1 were in the range of 0.037 ± 0.001–5.728 ± 0.043 mM. Ki constants for caspofungin acetate, amphotericin B, anidulafungin, and fluconazole were determined to be 0.0105 ± 0.0015 mM, 0.3206 ± 0.0196 mM, 0.1674 ± 0.0233 mM, and 2.5464 ± 0.1655 mM, respectively. The inhibition mechanism of amphotericin B was non-competitive, whereas anidulafungin was mixed type, and the others were competitive.

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Abbreviations

ALS:

Amyotrophic lateral sclerosis

BSA:

Bovine serum albumin

EU:

Enzyme unit

GF:

Gel filtration

GSH:

Glutathione

GST:

Glutathione-S-transferase

HDL:

High-density lipoprotein

IEX:

Ion exchange chromatography

MW:

Molecular weight

OPs:

Organophosphorus insecticides

PON:

Paraoxonase

SDS-PAGE:

Sodium dodecyl sulfate-polyacrylamide gel electrophoresis

SEC:

Size exclusion chromatography

SP:

Standard precision

ΔG Coulomb:

Coulombic energy

ΔG vdW:

van der Waals energy

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Acknowledgments

The authors thank Samet Karataş and Muhammed Kerem Türkeş for his kind help suggestions during the preparation of the manuscript.

Funding

This work was supported by the Research Fund of Erzincan Binali Yıldırım University (project number FBA-2017-501). The authors are grateful to Erzincan Binali Yıldırım University for financial support.

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  1. Department of Biochemistry, Faculty of Pharmacy, Erzincan Binali Yıldırım University, 24100, Erzincan, Turkey

    Cüneyt Türkeş

  2. Department of Biochemistry, Faculty of Pharmacy, Anadolu University, 26470, Eskişehir, Turkey

    Şükrü Beydemir

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  1. Cüneyt Türkeş
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Türkeş, C., Beydemir, Ş. Inhibition of Human Serum Paraoxonase-I with Antimycotic Drugs: In Vitro and In Silico Studies. Appl Biochem Biotechnol 190, 252–269 (2020). https://doi.org/10.1007/s12010-019-03073-3

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