Differential behavior of the sub-sites of cytochrome 450 active site in binding of substrates, and products (implications for coupling/uncoupling)

Narasimhulu, Shakunthala

doi:10.1016/j.bbagen.2006.09.018

Cited by 16 publications

(24 citation statements)

References 61 publications

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“…The loss of enzyme activity for so many compounds suggests that it may be due to mechanisms other than reactive or tight binding of metabolites. Uncoupling of the catalytic cycle (futile cycling) induced by binding, turnover of compounds, and associated generation of reactive oxygen species may be an additional mechanism for TDI (Narasimhulu, 2007). Our method (based on k obs at 10 M) correlates well with other methods for TDI risk assessment.…”

Section: Discussionsupporting

confidence: 51%

CYP3A Time-Dependent Inhibition Risk Assessment Validated with 400 Reference Drugs

Zimmerlin

Trunzer²,

Faller³

2011

Drug Metab Dispos

104

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ABSTRACT:Although reversible CYP3A inhibition testing is well established for predicting the drug-drug interaction potential of clinical candidates, time-dependent inhibition (TDI) has become the focus of drug designers only recently. Failure of several late-stage clinical candidates has been attributed to TDI, and this mechanism is also suspected to play a role in liver toxicities often observed in preclinical species. Measurement of enzyme inactivation rates (k inact and K I ) is technically challenging, and a great deal of variability can be found in the literature. In this article, we have evaluated the TDI potential for 400 registered drugs using a high-throughput assay format based on determination of the inactivation rate (k obs ) at a single concentration of test compound (10 M). The advantages of this new assay format are highlighted by comparison with data generated using the IC 50 shift assay, a current standard approach for preliminary assessment of TDI. With use of an empirically defined positive/negative k obs bin of 0.02 min ؊1, only 4% of registered drugs were found to be positive. This proportion increased to more than 20% when in-house lead optimization molecules were considered, emphasizing the importance of identifying this property in selection of promising drug candidates. Finally, it is suggested that the data and technology described here may be a good basis for building structure-activity relationships and in silico modeling.

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Section: Discussionsupporting

confidence: 51%

CYP3A Time-Dependent Inhibition Risk Assessment Validated with 400 Reference Drugs

Zimmerlin

Trunzer²,

Faller³

2011

Drug Metab Dispos

104

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“…The camphor monoxygenase P450cam catalyzes the 5-exo hydroxylation of camphor [33]. Its active site may be considered to have two functionally different subsites: the substrate binding region (site I) and the L 6 position of the iron to which oxygen binds upon reduction (site II) [33].…”

Section: Resultsmentioning

confidence: 99%

“…Its active site may be considered to have two functionally different subsites: the substrate binding region (site I) and the L 6 position of the iron to which oxygen binds upon reduction (site II) [33]. Allosteric interactions between these subsites are reflected in the fact that site I binding can inhibit site II ligation and vice versa.…”

Section: Resultsmentioning

confidence: 99%

Modular architecture of protein structures and allosteric communications: potential implications for signaling proteins and regulatory linkages

et al. 2007

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This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Modularity and allosteric communication

A new method for studying signal transmission between functional sites by decomposing protein structures into modules demonstrates that protein domains consist of modules interconnected by residues that mediate signaling through the shortest pathways.

Abstract Background: Allosteric communications are vital for cellular signaling. Here we explore a relationship between protein architectural organization and shortcuts in signaling pathways.

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“…Some metabolic enzymes, in particular CYP3A4, can exhibit non Michaelis-Menten characteristics in the presence of an inhibitor or an activator (in some cases it is the drug itself). CYP enzymes harbor at least two substrate-binding sites (15)(16)(17)(18). For some substrates, reaction patterns have been observed consistent with self-activation and/or self-inhibition.…”

Section: Simulated Metabolismmentioning

confidence: 75%

An In Silico Transwell Device for the Study of Drug Transport and Drug–Drug Interactions

Garmire

Hunt

2007

Pharm Res

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Differential behavior of the sub-sites of cytochrome 450 active site in binding of substrates, and products (implications for coupling/uncoupling)

Cited by 16 publications

References 61 publications

CYP3A Time-Dependent Inhibition Risk Assessment Validated with 400 Reference Drugs

CYP3A Time-Dependent Inhibition Risk Assessment Validated with 400 Reference Drugs

Modular architecture of protein structures and allosteric communications: potential implications for signaling proteins and regulatory linkages

An In Silico Transwell Device for the Study of Drug Transport and Drug–Drug Interactions

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