Recent density functional theory model calculations of drug metabolism by cytochrome P450

Li, Dongmei; Wang, Yong; Han, Keli

doi:10.1016/j.ccr.2012.01.016

Cited by 125 publications

(65 citation statements)

References 138 publications

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“…The mechanism of P450 enzymes, with oxidation mechanisms and inhibition has received particular attention [30][31][32][33][34][35][36]. Plant AOS and related atypical P450s in the prostaglandin H 2 to prostacyclin pathway have also been studied extensively.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic insights into the catalytic reaction of plant allene oxide synthase (pAOS) via QM and QM/MM calculations

Somboon

Ochiai

Treesuwan

et al. 2014

Journal of Molecular Graphics and Modelling

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Section: Introductionmentioning

confidence: 99%

Mechanistic insights into the catalytic reaction of plant allene oxide synthase (pAOS) via QM and QM/MM calculations

Somboon

Ochiai

Treesuwan

et al. 2014

Journal of Molecular Graphics and Modelling

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“…1 One particular class of enzymes with great relevance to biocatalysis and biodegradation are the cytochromes P450, which in the human body have functions that give them their primary purpose in the metabolism of harmful xenobiotics (drugs), as well as in the synthesis of hormones. 2 These enzymes form a high-valent iron(IV)–oxo heme cation radical as the active oxidant that performs a versatile set of reactions efficiently. 3 While metal–oxo complexes are generally thought to reside in their lower spin states in these hexacoordinated heme structures, actually the iron(IV)–oxo species in pentacoordinated nonheme enzymes typically exhibits a high-spin state.…”

Section: Introductionmentioning

confidence: 99%

Singlet versus Triplet Reactivity in an Mn(V)–Oxo Species: Testing Theoretical Predictions Against Experimental Evidence

et al. 2016

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Discerning the factors that control the reactivity of high-valent metal–oxo species is critical to both an understanding of metalloenzyme reactivity and related transition metal catalysts. Computational studies have suggested that an excited higher spin state in a number of metal–oxo species can provide a lower energy barrier for oxidation reactions, leading to the conclusion that this unobserved higher spin state complex should be considered as the active oxidant. However, testing these computational predictions by experiment is difficult and has rarely been accomplished. Herein, we describe a detailed computational study on the role of spin state in the reactivity of a high-valent manganese(V)–oxo complex with para-Z-substituted thioanisoles and utilize experimental evidence to distinguish between the theoretical results. The calculations show an unusual change in mechanism occurs for the dominant singlet spin state that correlates with the electron-donating property of the para-Z substituent, while this change is not observed on the triplet spin state. Minimum energy crossing point calculations predict small spin–orbit coupling constants making the spin state change from low spin to high spin unlikely. The trends in reactivity for the para-Z-substituted thioanisole derivatives provide an experimental measure for the spin state reactivity in manganese–oxo corrolazine complexes. Hence, the calculations show that the V-shaped Hammett plot is reproduced by the singlet surface but not by the triplet state trend. The substituent effect is explained with valence bond models, which confirm a change from an electrophilic to a nucleophilic mechanism through a change of substituent.

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“…[28][29][30][31] The study of solvent e®ect on the stability of isomers indicates, (I)-isomer is still the most stable one among all the isomers. On the other hand, ÁE 1 values decrease and ÁE 2 values increase, as polarity of solvent increase Among the transition states, TSb state changes considerably with polarity of solvent.…”

Section: -2mentioning

confidence: 99%

Tautomeric transformations and reactivity of isoindole and sila-indole: A computational study

Ghiasi

Fashami

2014

J. Theor. Comput. Chem.

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In this work, the tautomeric transformations and reactivity of isoindole and sila-isoindole molecules has been explored using the B3LYP/6-311G(d,p) level of theory in gas and solution phases. These calculations show that isoindole isomer has more stability rather than 1-h-isoindole. There is identical trend in silated species. The frontier molecular orbitals (FMO) and band gap energy calculations were performed at the B3LYP/6-311G(d,p) level in gas and various solvent. Solvent e®ects have been analyzed by using the self-consistent reaction¯eld (SCRF) method based on polarizable continuum model (PCM) in chloroform, chlorobenzene, dichloromethane and tetrahydrofurane. Thermodynamic parameters calculated at room temperature have been analyzed. Also, electron a±nities were computed. Local reactivity descriptors as Fukui functions (f þ k ; f À k f 0 k ) local softness (s þ k ; s À k s 0 k ) and electrophilicity indices (! þ k ; ! À k ; ! 0 k ) analyses are performed to¯nd out the reactive sites within molecule. Density functional theory (DFT) calculations were performed to compute nitrogen-14 nuclear quadrupole resonance (NQR) spectroscopy parameters.

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Recent density functional theory model calculations of drug metabolism by cytochrome P450

Cited by 125 publications

References 138 publications

Mechanistic insights into the catalytic reaction of plant allene oxide synthase (pAOS) via QM and QM/MM calculations

Mechanistic insights into the catalytic reaction of plant allene oxide synthase (pAOS) via QM and QM/MM calculations

Singlet versus Triplet Reactivity in an Mn(V)–Oxo Species: Testing Theoretical Predictions Against Experimental Evidence

Tautomeric transformations and reactivity of isoindole and sila-indole: A computational study

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