An attempt to evaluate the effect of proton-coupled electron transfer on the H-abstraction step of the reaction between 1,1-dimethylhydrazine and cytochrome P450 compound I

Hirao, Hajime; Chuanprasit, Pratanphorn

doi:10.1016/j.cplett.2014.12.027

Cited by 12 publications

(19 citation statements)

References 43 publications

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“…It is obvious that two π-type lobes on both of the substrate nitrogen atom and the oxidant oxygen atom are perpendicular to the N-H-O axis, which is a typical feature of the PCET transition state. This is similar to the findings of previous studies (Mayer et al, 2002 ; Usharani et al, 2013 ; Hirao and Chuanprasit, 2015 ).…”

Section: Resultssupporting

confidence: 93%

“…Moreover, such N -HAT mechanism was subsequently validated by Hirao et al in their investigation on P450 inactivation by 1,1-dimethylhydrazine (Hirao et al, 2013a ). However, previous investigations have revealed that there might be an alternative proton-coupled electron transfer (PCET) mechanism for the polar X-H (X = O, N) bond activation (Mayer et al, 2002 ; Usharani et al, 2013 ; Hirao and Chuanprasit, 2015 ; Li et al, 2015 ). Thus, an obvious question to be answered is: Ring-opening of BCA is initiated by a direct HAT mechanism or a PCET one?…”

Section: Introductionmentioning

confidence: 99%

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Suicide Inhibition of Cytochrome P450 Enzymes by Cyclopropylamines via a Ring-Opening Mechanism: Proton-Coupled Electron Transfer Makes a Difference

Zhang

Liu

et al. 2017

Front. Chem.

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N-benzyl-N-cyclopropylamine (BCA) has been attracting great interests for decades for its partial suicide inactivation role to cytochrome P450 (P450) via a ring-opening mechanism besides acting as a role of normal substrates. Understanding the mechanism of such partial inactivation is vital to the clinical drug design. Thus, density functional theoretical (DFT) calculations were carried out on such P450-catalyzed reactions, not only on the metabolic pathway, but on the ring-opening inactivation one. Our theoretical results demonstrated that, in the metabolic pathway, besides the normal carbinolamine, an unexpected enamine was formed via the dual hydrogen abstraction (DHA) process, in which the competition between rotation of the H-abstracted substrate radical and the rotation of hydroxyl group of the protonated Cpd II moiety plays a significant role in product branch; In the inactivation pathway, the well-noted single electron transfer (SET) mechanism-involved process was invalidated for its high energy barrier, a proton-coupled electron transfer [PCET(ET)] mechanism plays a role. Our results are consistent with other related theoretical works on heteroatom-hydrogen (X-H, X = O, N) activation and revealed new features. The revealed mechanisms will play a positive role in relative drug design.

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Section: Resultssupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Suicide Inhibition of Cytochrome P450 Enzymes by Cyclopropylamines via a Ring-Opening Mechanism: Proton-Coupled Electron Transfer Makes a Difference

Zhang

Liu

et al. 2017

Front. Chem.

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“…According to the BDE vs E a trend, it is expected to observe a similar reactivity pattern for hydrogen abstraction in N–H, O–H, and C–H bonds, but DFT studies exhibited a considerable difference in activation energy for these groups. For example, the BDE of cyclohexene (C–H) and 1,1-dimethylhydrazine (N–H) is relatively equal (80–82 kcal mol –1 calculated at G4 level of theory), but the hydrogen abstraction transition-state energy for 1,1-dimethylhydrazine (∼0.0 kcal mol –1 ) is considerably lower than cyclohexene (∼9.9 kcal mol –1 ) …”

Section: Proton-coupled Electron Transfermentioning

confidence: 99%

Mechanism-Based Inactivation of Cytochrome P450 Enzymes: Computational Insights

Mirzaei

Ivanov

Mirzaei

2021

Chem. Res. Toxicol.

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Mechanism-based inactivation (MBI) refers to the metabolic bioactivation of a xenobiotic by cytochrome P450s to a highly reactive intermediate which subsequently binds to the enzyme and leads to the quasi-irreversible or irreversible inhibition. Xenobiotics, mainly drugs with specific functional units, are the major sources of MBI. Two possible consequences of MBI by medicinal compounds are drug–drug interaction and severe toxicity that are observed and highlighted by clinical experiments. Today almost all of these latent functional groups (e.g., thiophene, furan, alkylamines, etc.) are known, and their features and mechanisms of action, owing to the vast experimental and theoretical studies, are determined. In the past decade, molecular modeling techniques, mostly density functional theory, have revealed the most feasible mechanism that a drug undergoes by P450 enzymes to generate a highly reactive intermediate. In this review, we provide a comprehensive and detailed picture of computational advances toward the elucidation of the activation mechanisms of various known groups with MBI activity. To this aim, we briefly describe the computational concepts to carry out and analyze the mechanistic investigations, and then, we summarize the studies on compounds with known inhibition activity including thiophene, furan, alkylamines, terminal acetylene, etc. This study can be reference literature for both theoretical and experimental (bio)chemists in several different fields including rational drug design, the process of toxicity prevention, and the discovery of novel inhibitors and catalysts.

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“…N -Oxidation is also an important reaction in drug metabolism to detoxify drugs by CYPs. Several experimental and theoretical studies were reported on N -oxidation reactions. ,− Quantum chemical studies on the mechanism of N -oxidation using model oxidant Cpd I were performed extensively for primary, ,− secondary, and tertiary amines, ,− , hydrazine, ,, and aromatic amines, ,, and the reported barriers for N -oxidation are in the range of 10–20 kcal/mol. In the case of TZ, the nucleophilicity originating from the N -center is less than that of the C 5 center (Table ).…”

Section: Quantum Chemical Studiesmentioning

confidence: 99%

Reactive Metabolites from Thiazole-Containing Drugs: Quantum Chemical Insights into Biotransformation and Toxicity

Jaladanki

Khatun

Gohlke

et al. 2021

Chem. Res. Toxicol.

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Drugs containing thiazole and aminothiazole groups are known to generate reactive metabolites (RMs) catalyzed by cytochrome P450s (CYPs). These RMs can covalently modify essential cellular macromolecules and lead to toxicity and induce idiosyncratic adverse drug reactions. Molecular docking and quantum chemical hybrid DFT study were carried out to explore the molecular mechanisms involved in the biotransformation of thiazole (TZ) and aminothiazole (ATZ) groups leading to RM epoxide, S-oxide, N-oxide, and oxaziridine. The energy barrier required for the epoxidation is 13.63 kcal/mol, that is lower than that of S-oxidation, N-oxidation, and oxaziridine formation (14.56, 17.90, and 20.20, kcal/mol respectively). The presence of the amino group in ATZ further facilitates all the metabolic pathways, for example, the barrier for the epoxidation reaction is reduced by ∼2.5 kcal/mol. Some of the RMs/their isomers are highly electrophilic and tend to form covalent bonds with nucleophilic amino acids, finally leading to the formation of metabolic intermediate complexes (MICs). The energy profiles of these competitive pathways have also been explored.

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An attempt to evaluate the effect of proton-coupled electron transfer on the H-abstraction step of the reaction between 1,1-dimethylhydrazine and cytochrome P450 compound I

Cited by 12 publications

References 43 publications

Suicide Inhibition of Cytochrome P450 Enzymes by Cyclopropylamines via a Ring-Opening Mechanism: Proton-Coupled Electron Transfer Makes a Difference

Suicide Inhibition of Cytochrome P450 Enzymes by Cyclopropylamines via a Ring-Opening Mechanism: Proton-Coupled Electron Transfer Makes a Difference

Mechanism-Based Inactivation of Cytochrome P450 Enzymes: Computational Insights

Reactive Metabolites from Thiazole-Containing Drugs: Quantum Chemical Insights into Biotransformation and Toxicity

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