Density Functional Theory Study on the Formation of Reactive Benzoquinone Imines by Hydrogen Abstraction

Leth, Rasmus; Rydberg, Patrik; Jørgensen, Flemming Steen; Olsen, Lars

doi:10.1021/ci500653b

Cited by 8 publications

(5 citation statements)

References 44 publications

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“…Initial studies found very weak correlations with cLog D 7.4 and TPSA but no correlation with calculated human liver microsome stability . A recent report used computational methods to investigate the hydrogen abstraction mechanism of acetaminophen and related drugs to form reactive quinone imines . The authors demonstrated that low (<5 kJ/mol) transition-state (TS) activation barriers for the first hydrogen abstraction in these compounds calculated using a porphyrin model correlate well with experimentally observed issues with reactive metabolites either by depletion of GSH, leading to hepatotoxicity, or by inactivation of CYP enzymes, leading to drug–drug interactions. − It was further shown that there is a linear correlation between relative phenolic O–H bond dissociation enthalpies (ΔBDEs) and the transition state activation barrier with an R 2 value of 0.72, as previously observed in other systems. − Taken as a whole, this suggested that ΔBDEs of phenolic O–H could be used to predict the formation of reactive metabolites and help prioritize the choice of substituents and/or ring systems prior to synthesis.…”

Section: Results and Discussionmentioning

confidence: 95%

Strategies to Mitigate the Bioactivation of Aryl Amines

Zhang¹,

Crawford²,

Landry³

et al. 2020

Chem. Res. Toxicol.

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The bioactivation of xenobiotics to yield reactive metabolites can lead to tolerability and toxicity concerns within a drug discovery program. Development of strategies for mitigating the metabolic liability of commonly encountered toxicophores, such as anilines, relies on an understanding of the relative tendency of these functionalities to undergo bioactivation. In this report, we present the first systematic study of the structure−activity relationships of the bioactivation of aryl amine fragments (molecular weight < 250 Da) using a glutathione (GSH) trapping assay in the presence of human liver microsomes and the reduced form of nicotinamide adenine dinucleotide phosphate. This study demonstrates that conversion of anilines to nitrogencontaining heteroarylamines results in a lower abundance of GSH conjugates in the order phenyl > pyrimidine ≈ pyridine > pyridazine. Introduction of electron-withdrawing functionality on the aromatic ring had a less pronounced effect on the extent of GSH conjugation. Examination of more drug-like compounds sourced from in-house drug discovery programs revealed similar trends in bioactivation between matched pairs containing (hetero)aryl amines. This study provides medicinal chemists with insights and qualitative guidance for the minimization of risks related to aryl amine metabolism.

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Section: Results and Discussionmentioning

confidence: 95%

Strategies to Mitigate the Bioactivation of Aryl Amines

Zhang¹,

Crawford²,

Landry³

et al. 2020

Chem. Res. Toxicol.

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“…Although additional functionals and QM methods have been developed since B3LYP, comparisons suggest that B3LYP is well suited and provides consistency with previous studies. 53,54 The most reactive sites from the DFT calculations on the four compounds studied in this paper are the aromatic hydroxylation reactions in 5 and 4′ positions which, including the dispersion, are as reactive as the Me-2′ and Me-3′ hydroxylation. From the MD simulations, most of the aromatic sites are generally equally accessible.…”

Section: ■ Discussionmentioning

confidence: 99%

Both Reactivity and Accessibility Are Important in Cytochrome P450 Metabolism: A Combined DFT and MD Study of Fenamic Acids in BM3 Mutants

Leth

Ercig

Olsen

et al. 2019

J. Chem. Inf. Model.

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Cytochrome P450 102A1 from Bacillus megaterium (BM3) is a fatty acid hydroxylase that has one of the highest turnover rates of any mono-oxygenase. Recent studies have shown how mutants of BM3 can produce metabolites of known drug compounds similar to those observed in humans. Single-point mutations in the binding pocket change the regioselective metabolism of fenamic acids from aromatic hydroxylation to aliphatic hydroxylation. This study is concerned with the individual contribution from accessibility and reactivity for drug metabolism with a future goal to develop fast methods for prediction. For a BM3 M11 mutant as well as the M11 V87F and M11 V87I mutants, we studied the metabolism of the nonsteroidal anti-inflammatory drugs (NSAIDs) mefenamic acid, meclofenamic acid, tolfenamic acid, and diclofenac. Density functional theory (DFT; B3LYP and B3LYP-D3) calculations for all possible reactions were performed using a porphyrin model reacting with the four substrates. Molecular dynamics (MD) simulations were used to determine the potential sites of metabolism that are accessible. Finally, we combine reactivity and accessibility for each potential site to interpret the experimentally determined metabolism. Generally, the 3 and 5 positions (on the ring containing the acidic substituent) and the 2′, 3′, and 4′ positions are most reactive, whereas 4, 5, 3′, and 4′ are most accessible. Combining reactivity and accessibility show that the 5, 3′, and 4′ positions are predicted to be most prone to be metabolized, in agreement with experimentally observed data. Reactivity seems to be the dominant factor in the CYP-mediated metabolism of these NSAIDs, which is consistent with previously published methods based solely on reactivity.

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“…Activation barriers were calculated at the DFT/B3LYP − and B3LYP-D3 levels of theory with a protocol similar to the one adopted by Leth et al Cpd I was modeled as an Fe 5+ ion embedded in a porphyrin ring without side chains and with CH 3 S – and O 2– as axial ligands. , The iron ion of POA was formally Fe 2+ , and the formal charge of the system was set to −2 according to the data published by Rydberg et al A simplified substrate formed only by rings C and D was used in the calculations mimicking the full steroidal scaffold. Geometry optimizations, vibrational analyses, and solvent calculations were performed in the gas phase using the 6-31G(d) basis set for all atoms except iron, for which the double-ζ basis set of Schäfer et al .…”

Section: Computational Methodsmentioning

confidence: 99%

“…19 ■ COMPUTATIONAL METHODS DFT Calculations. Activation barriers were calculated at the DFT/B3LYP 20−22 and B3LYP-D3 23 levels of theory with a protocol similar to the one adopted by Leth et al 24 Cpd I was modeled as an Fe 5+ ion embedded in a porphyrin ring without side chains and with CH 3 S − and O 2− as axial ligands. 4,24 The iron ion of POA was formally Fe 2+ , and the formal charge of the system was set to −2 according to the data published by Rydberg et al 25 A simplified substrate formed only by rings C and D was used in the calculations mimicking the full steroidal scaffold.…”

Section: ■ Introductionmentioning

confidence: 99%

Mechanism of Cytochrome P450 17A1-Catalyzed Hydroxylase and Lyase Reactions

Bonomo

Jørgensen

Olsen

2017

J. Chem. Inf. Model.

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Cytochrome P450 17A1 (CYP17A1) catalyzes C17 hydroxylation of pregnenolone and progesterone and the subsequent C17-C20 bond cleavage (lyase reaction) to form androgen precursors. Compound I (Cpd I) and peroxo anion (POA) are the heme-reactive species underlying the two reactions. We have characterized the reaction path for both the hydroxylase and lyase reactions using density functional theory (DFT) calculations and the enzyme-substrate interactions by molecular dynamics (MD) simulations. Activation barriers for positions subject to hydroxylase reaction have values close to each other and span from 54 to 60 kJ·mol with a small preference for 17α hydroxylation, in agreement with experimental observations. For the lyase reaction, two different types of mechanisms, concerted and stepwise, with identical activation energies (87 kJ·mol) were identified. Embedding the DFT-optimized transition states (TSs) for the two reactions into the active site of CYP17A1 showed that the TS for the C17 hydroxylation needs to be distorted by 13 kJ·mol, whereas the TS for the 17,20 lyase reaction easily can be accommodated in the protein. Finally, differences in the hydrogen-bond pattern of the substrates were detected both in the CYP17A1-Cpd I and CYP17A1-POA complexes, with the former found to be more pivotal for the hydroxylation site than the latter, suggesting a possible explanation for the slower conversion of CYP17A1 for 17α-hydroxyprogesterone over 17α-hydroxypregnenolone. The results support the concept that the selectivity of the steroidogenic CYPs is ruled by direct interactions with the enzyme, in contrast to the selectivity of drug-metabolizing CYPs, where the reactivity of the substrates dominates.

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Density Functional Theory Study on the Formation of Reactive Benzoquinone Imines by Hydrogen Abstraction

Cited by 8 publications

References 44 publications

Strategies to Mitigate the Bioactivation of Aryl Amines

Strategies to Mitigate the Bioactivation of Aryl Amines

Both Reactivity and Accessibility Are Important in Cytochrome P450 Metabolism: A Combined DFT and MD Study of Fenamic Acids in BM3 Mutants

Mechanism of Cytochrome P450 17A1-Catalyzed Hydroxylase and Lyase Reactions

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