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Quantum Simulations Reveal Fungicide Metabolism Pathways

In an article recently published in the journal Ecotoxicology and Environmental Safety, researchers performed computational simulations, including quantum mechanics/molecular mechanics (QM/MM) calculations, to reveal the chiral triazole fungicides’ enantioselective metabolism by human cytochrome P450 (CYP450) enzymes.

Quantum Simulations Reveal Fungicide Metabolism Pathways

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Enantioselective Metabolism of Triazole Fungicides

The widespread use of pesticides often leads to lasting environmental contamination and the build-up of these chemicals in living organisms. Currently, about one-third of registered pesticides contain one or more chiral centers. Triazole fungicides, frequently used to control crop diseases caused by various plant pathogens, are largely chiral, with one or more stereogenic centers. These fungicides are commonly released into the environment as mixtures of equimolar enantiomers.

Toxicological research has revealed that these fungicides can have harmful effects, including endocrine disruption, developmental and reproductive toxicity, and liver toxicity in mammals and other organisms. A notable example is the chiral triazole fungicide tebuconazole (TEB), which the US Environmental Protection Agency (EPA) has classified as a potential carcinogen. TEB has been associated with various adverse effects on non-target organisms.

The enantioselectivity of TEB—its different effects depending on its enantiomers—has been observed in its degradation, toxicity, and accumulation. This enantioselectivity underscores the importance of studying how each enantiomer of TEB is metabolized and the potential health risks from human exposure to TEB.

Although TEB metabolism in mammals has been experimentally validated, the specific enantioselective biotransformation of S- and R-TEB by certain CYP450 enzymes remains unclear. CYP450s, primarily found in liver microsomes, are a major family of phase-I metabolic enzymes. They use a reactive iron (IV)-oxo porphyrin cation radical species (Cpd I) to catalyze the biotransformation of various xenobiotics, including chiral chemicals.

The Study

In this study, researchers used advanced in silico simulations to explore the enantioselective metabolism and binding interactions of TEB enantiomers with key human CYP450 isoforms, specifically 3A4, 2E1, 2B6, and CYP1A2. TEB was chosen as a representative chiral triazole fungicide for this investigation.

The researchers employed a comprehensive computational approach that combined molecular docking, QM/MM calculations, and molecular dynamics (MD) simulations. The goal was to uncover the differences in biotransformation profiles and binding interactions between the S- and R-TEB enantiomers at the atomic and molecular levels.

Molecular docking calculations were performed using the AutoDock Vina program to predict the initial binding modes of S-TEB and R-TEB within the four CYP450 isoforms. These isoforms were selected due to their potential roles in the biotransformation of various chiral compounds in humans.

For MD simulations, the researchers used the Amber22 program with the ff14SB force field to dynamically assess the binding interactions and conformations of S- and R-TEB within the CYP450 isoforms. The force field parameters for Cpd I and TEB were sourced from existing literature and generated using the Antechamber tool with restricted electrostatic potential charges.

QM/MM calculations, performed with the ChemShell package, provided detailed insights into the mechanistic aspects of R/S-TEB enantioselective biotransformation mediated by CYP450s. ChemShell integrates the DL_POLY program for the MM region and the Turbomole program for the QM region.

In the QM region, the study focused on the Cys residue bound to the iron atom and R/S-TEB, using the spin-unrestricted B3LYP density functional for calculations. The MM region included the remaining atoms of the system, described by the Amber force field.

To determine transition states and local minima along the reaction pathways, researchers used the geometry optimizer DL-FIND. They also applied an electrostatic-embedding protocol to account for the effects of MM charges on the QM region and addressed the QM/MM boundary using hydrogen link atoms and a charge shift model.

Study Contributions

In summary, this study provides significant insights into the enantioselective metabolism and binding specificity of TEB enantiomers by CYP450s. The MD simulations effectively delineated the binding preferences of S- and R-TEB, revealing that van der Waals interactions with hydrophobic residues are crucial for robust ligand binding.

QM/MM calculations identified C2-methyl hydroxylation as the dominant metabolic pathway, with triazole epoxidation and C6-hydroxylation being less feasible. The study highlighted that hydroxy-R-TEB primarily results from the metabolism of R-TEB by CYP450 isoforms 3A4, 2E1, and 1A2, while hydroxy-S-TEB is mainly produced by 2B6.

Overall, CYP450s exhibit a kinetic preference for R-TEB metabolism over S-TEB. These findings advance our understanding of the metabolic fate and binding characteristics of chiral TEB and provide a foundation for further research on assessing human health risks related to TEB exposure.

Journal Reference

Chen, Y. et al. (2024). Computational simulations uncover enantioselective metabolism of chiral triazole fungicides by human CYP450 enzymes: A case study of tebuconazole. Ecotoxicology and Environmental Safety, 284, 116865. DOI: 10.1016/j.ecoenv.2024.116865, https://www.sciencedirect.com/science/article/pii/S0147651324009412

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Samudrapom Dam

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Samudrapom Dam

Samudrapom Dam is a freelance scientific and business writer based in Kolkata, India. He has been writing articles related to business and scientific topics for more than one and a half years. He has extensive experience in writing about advanced technologies, information technology, machinery, metals and metal products, clean technologies, finance and banking, automotive, household products, and the aerospace industry. He is passionate about the latest developments in advanced technologies, the ways these developments can be implemented in a real-world situation, and how these developments can positively impact common people.

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