Regioselectivity preference of testosterone hydroxylation by cytochrome P450 3A4

Zhang, Yan; Morisetti, Phani; Kim, Jeffery; Smith, Lynelle P.; Lin, Hai

doi:10.1007/s00214-008-0480-1

Cited by 11 publications

(16 citation statements)

References 72 publications

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“…The activation barriers for the 6β, 2β, 15β and 1β sites are 5.3, 9.9, 10.2 and 13.5 kcal mol −1 , respectively, which are in good agreement with the experimental data . For the four β sites, the activation barriers are also very close to those calculated in the previous study when the dispersion interaction is not considered . The high reactivity of the 6β and 2β sites do not come as a surprise because of the electron‐delocalization effect of the conjugated carbonyl moiety, which significantly stabilizes the TS structures.…”

Section: Resultssupporting

confidence: 86%

Mechanistic Insights into the Regio‐ and Stereoselectivities of Testosterone and Dihydrotestosterone Hydroxylation Catalyzed by CYP3A4 and CYP19A1

Tang

et al. 2020

Chemistry A European J

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The hydroxylation of nonreactive CÀHb onds can be easily catalyzed by av ariety of metalloenzymes, especially cytochrome P450s (P450s). The mechanism of P450 mediated hydroxylation has been intensively studied, both experimentally and theoretically.H owever,u nderstandingt he regio-and stereoselectivities of substrates hydroxylated by P450s remains ag reat challenge. Herein, we use am ultiscale modeling approach to investigatet he selectivity of testosterone (TES) and dihydrotestosterone (DHT)h ydroxylation catalyzed by two important P450s,C YP3A4 and CYP19A1. For CYP3A4, two distinct binding modes for TES/DHTw ere predicted by dockings and molecular dynamics simulations, in whicht he experimentally identified sites of metabolism of TES/DHTc an access to the catalytic center.T he regio-and stereoselectivities of TES/DHTh ydroxylation were further evaluated by quantum mechanical andO NIOM calculations. For CYP19A1, we found that sites 1b,2 b and 19 can access the catalytic center, with the intrinsic reactivity 2b > 1b > 19. However, ourO NIOM calculations indicate that the hydroxylation is favored at site 19 for both TES and DHT,w hich is consistentw ith the experiments and reflects the importance of the catalytic environment in determining the selectivity. Our study unravels the mechanism underlyingt he selectivity of TES/DHT hydroxylationm ediated by CYP3A4 and CYP19A1a nd is helpful for understanding the selectivity of other substrates that are hydroxylatedb yP450s.[a] J.

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Section: Resultssupporting

confidence: 86%

Mechanistic Insights into the Regio‐ and Stereoselectivities of Testosterone and Dihydrotestosterone Hydroxylation Catalyzed by CYP3A4 and CYP19A1

Tang

et al. 2020

Chemistry A European J

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“…Theoretical calculations were applied to CYP3A4 to estimate the activation energy of the intermediate formation and predict the binding modes for indapamide and 4-aminopiperidine [85, 86], investigate interaction between nevirapine, carbamazepine and endogenous steroids [97], explore features of the catalytic oxyferryl species (compound I) [98], model the regioselectivity preference of testosterone hydroxylation [99], and test the reactivity of various sites on flunitrazepam and progesterone [100]. …”

Section: 3 Computational Approachesmentioning

confidence: 99%

Current Approaches for Investigating and Predicting Cytochrome P450 3A4-Ligand Interactions

Sevrioukova

Poulos

2015

Advances in Experimental Medicine and Biology

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Cytochrome P450 3A4 (CYP3A4) is the major and most important drug-metabolizing enzyme in humans that oxidizes and clears over a half of all administered pharmaceuticals. This is possible because CYP3A4 is promiscuous with respect to substrate binding and has the ability to catalyze diverse oxidative chemistries in addition to traditional hydroxylation reactions. Furthermore, CYP3A4 binds and oxidizes a number of substrates in a cooperative manner and can be both induced and inactivated by drugs. In vivo, CYP3A4 inhibition could lead to undesired drug-drug interactions and drug toxicity, a major reason for late-stage clinical failures and withdrawal of marketed pharmaceuticals. Owing to its central role in drug metabolism, many aspects of CYP3A4 catalysis have been extensively studied by various techniques. Here, we give an overview of experimental and theoretical methods currently used for investigation and prediction of CYP3A4-ligand interactions, a defining factor in drug metabolism, with an emphasis on the problems addressed and conclusions derived from the studies.

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“…Later, the Yoshizawa group studied the kinetic isotope effect of the C H bond activation of alkane [26,27] and the mechanism of camphor hydroxylation by Cpd I [28]. Since then, P450-catalyzed substrate metabolism has been widely studied using the DFT method, including alkane hydroxylation [28,29], alkene epoxidation [30][31][32][33], aromatic hydroxylation [34][35][36][37][38], S-, N-, O-oxidation and dealkylation [39][40][41][42][43][44], dehalogenation of perhalogenated benzene [45], prostaglandin H 2 isomerization [46], and so on.…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Han

2012

Coordination Chemistry Reviews

132

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Regioselectivity preference of testosterone hydroxylation by cytochrome P450 3A4

Cited by 11 publications

References 72 publications

Mechanistic Insights into the Regio‐ and Stereoselectivities of Testosterone and Dihydrotestosterone Hydroxylation Catalyzed by CYP3A4 and CYP19A1

Mechanistic Insights into the Regio‐ and Stereoselectivities of Testosterone and Dihydrotestosterone Hydroxylation Catalyzed by CYP3A4 and CYP19A1

Current Approaches for Investigating and Predicting Cytochrome P450 3A4-Ligand Interactions

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

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