Molecular characterization of CYP2B6 substrates

Sean Ekins; Manisha Iyer; Matthew D Krasowski; Evan D Kharasch

doi:10.2174/138920008784746346

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Molecular characterization of CYP2B6 substrates

Journal article

Peer reviewed

Molecular characterization of CYP2B6 substrates

Sean Ekins, Manisha Iyer, Matthew D Krasowski and Evan D Kharasch

Current drug metabolism, Vol.9(5), pp.363-373

06/2008

DOI: 10.2174/138920008784746346

PMCID: PMC2426921

PMID: 18537573

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Abstract

CYP2B6 has not been as fully characterized at the molecular level as other members of the human cytochrome P450 family. As more widely used in vitro probes for characterizing the involvement of this enzyme in the metabolism of xenobiotics have become available, the number of molecules identified as CYP2B6 substrates has increased. In this study we have analyzed the available kinetic data generated by multiple laboratories with human recombinant expressed CYP2B6 and along with calculated molecular properties derived from the ChemSpider database, we have determined the molecular features that appear to be important for CYP2B6 substrates. In addition we have applied 2D and 3D QSAR methods to generate predictive pharmacophore and 2D models. For 28 molecules with K(m) data, the molecular weight (mean +/- SD) is 253.78+/-74.03, ACD/logP is 2.68+/-1.51, LogD(pH 5.5) is 1.51+/-1.43, LogD(pH 7.4) is 2.02+/-1.25, hydrogen bond donor (HBD) count is 0.57 +/-0.57, hydrogen bond acceptor (HBA) count is 2.57+/-1.37, rotatable bonds is 3.50+/-2.71 and total polar surface area (TPSA) is 27.63+/-19.42. A second set of 15 molecules without K(m) data possessed similar mean molecular property values. These properties are comparable to those of a set of 21 molecules used in a previous pharmacophore modeling study (Ekins et al., J Pharmacol Exp Ther 288 (1), 21-29, 1999). Only the LogD and HBD values were statistically significantly different between these different datasets. We have shown that CYP2B6 substrates are generally small hydrophobic molecules that are frequently central nervous system active, which may be important for drug discovery research.

Pharmaceutical Preparations - metabolism

Animals

Computer Simulation

Humans

Models, Molecular

Substrate Specificity

Catalysis

Oxidoreductases, N-Demethylating - metabolism

Cytochrome P-450 CYP2B6

Quantitative Structure-Activity Relationship

Aryl Hydrocarbon Hydroxylases - metabolism

Details

Title: Subtitle: Molecular characterization of CYP2B6 substrates
Creators: Sean Ekins - Collaborations in Chemistry, 601 Runnymede Ave, Jenkintown, PA 19046. USA. ekinssean@yahoo.com
Manisha Iyer
Matthew D Krasowski
Evan D Kharasch
Resource Type: Journal article
Publication Details: Current drug metabolism, Vol.9(5), pp.363-373
DOI: 10.2174/138920008784746346
PMID: 18537573
PMCID: PMC2426921
NLM abbreviation: Curr Drug Metab
ISSN: 1389-2002
Publisher: Netherlands
Grant note: R01DA14211 / NIDA NIH HHS K08 GM074238-01A1 / NIGMS NIH HHS K24 DA000417-09 / NIDA NIH HHS K24 DA000417-08 / NIDA NIH HHS R01 DA014211 / NIDA NIH HHS K08 GM074238-02 / NIGMS NIH HHS R01 DA014211-06 / NIDA NIH HHS K08 GM074238 / NIGMS NIH HHS K24 DA000417 / NIDA NIH HHS R01 DA014211-05 / NIDA NIH HHS K24DA 00417 / NIDA NIH HHS K08-GM074238 / NIGMS NIH HHS
Language: English
Date published: 06/2008
Academic Unit: Pathology
Record Identifier: 9984047763602771

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