Cytochrome P450 2C9 type II binding studies on quinoline-4-carboxamide analogues

Chi-Chi Peng; Jonathan L Cape; Tom Rushmore; Gregory J Crouch; Jeffrey P Jones

doi:10.1021/jm8011257

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Cytochrome P450 2C9 type II binding studies on quinoline-4-carboxamide analogues

Journal article

Open access

Peer reviewed

Cytochrome P450 2C9 type II binding studies on quinoline-4-carboxamide analogues

Chi-Chi Peng, Jonathan L Cape, Tom Rushmore, Gregory J Crouch and Jeffrey P Jones

Journal of medicinal chemistry, Vol.51(24), pp.8000-8011

12/25/2008

DOI: https://doi.org/10.1021/jm8011257

Handle:

https://hdl.handle.net/2376/113069

PMCID: PMC2630467

PMID: 19053752

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Abstract

Cytochrome P-450 CYP2C9

Catalytic Domain

Chemistry, Pharmaceutical - methods

Humans

Iron - chemistry

Molecular Conformation

Quinolines - chemistry

Imidazoles - chemistry

Models, Molecular

Substrate Specificity

Structure-Activity Relationship

Arginine - chemistry

Aryl Hydrocarbon Hydroxylases - metabolism

Heme - chemistry

Drug Design

Protein Binding

Aryl Hydrocarbon Hydroxylases - chemistry

CYP2C9 is a significant P450 protein responsible for drug metabolism. With the increased use of heterocyclic compounds in drug design, a rapid and efficient predrug screening of these potential type II binding compounds is essential to avoid adverse drug reactions. To understand binding modes, we use quinoline-4-carboxamide analogues to study the factors that determine the structure-activity relationships. The results of this study suggest that the more accessible pyridine with the nitrogen para to the linkage can coordinate directly with the ferric heme iron, but this is not seen for the meta or ortho isomers. The pi-cation interaction of the naphthalene moiety and Arg 108 residue may also assist in stabilizing substrate binding within the active-site cavity. The type II substrate binding affinity is determined by the combination of steric, electrostatic, and hydrophobicity factors; meanwhile, it is enhanced by the strength of lone pair electrons coordination with the heme iron.

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Details

Title: Cytochrome P450 2C9 type II binding studies on quinoline-4-carboxamide analogues
Creators: Chi-Chi Peng - Department of Chemistry, Washington State University, P.O. Box 644630, Pullman, Washington 99164-4630, USA
Jonathan L Cape
Tom Rushmore
Gregory J Crouch
Jeffrey P Jones
Publication Details: Journal of medicinal chemistry, Vol.51(24), pp.8000-8011
Academic Unit: Chemistry, Department of
Publisher: United States
Grant note: R01 GM084546 / NIGMS NIH HHS P01 GM032165 / NIGMS NIH HHS GM032165 / NIGMS NIH HHS R01 GM084546-11 / NIGMS NIH HHS GM084546 / NIGMS NIH HHS
Identifiers: 99900547915101842
Language: English
Resource Type: Journal article