A three-dimensional molecular template for substrates of human cytochrome P450 involved in debrisoquine 4-hydroxylation

Suhail A. Islam, C. Roland Wolf, Martin S. Lennard, Michael J.E. Sternberg (Lead / Corresponding author)

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

A three-dimensional molecular template has been generated for substrates of human debrisoquine Chydroxylase cytochrome P450 (CYP2D6). This template defines the stereochemical requirements for CYP2D6 substrates in terms of the volume occupied and positions of key atoms. The modelling was based on the X-ray crystallographic coordinates of the location of the attacked C5 atom of camphor in relation to the haem in cytochrome P450 cam. Interactive molecular graphics combined with energy calculations were used to identify allowed conformers to superpose known CYP2D6 substrates to yield a molecular template. This model takes into account the site of attack of the known substrates and the requirement for a protonated nitrogen atom to interact with an anion site of the potein. A nitrogen-anion distance of between 2.5 and 4.5 Å was allowed for the interaction. The substrates modelled were cardiovascular drugs (debrisoquine, sparteine, guanoxan and perhexiline), βadrenergic blocking agents (bufuralol and propranolol), tricyclic antidepressants (desipramine, amitriptyline and nortriptyline) and other miscellaneous cornpour (phenformin, methoxyamphetamine, codeine and dextromethorphan). The template generated in this manner was then used to determine the likelihood that certain other compounds were substrates for CYP2D6. A carcinogenic protein pyrolysate product, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), did not fit the template and is therefore unlikely to be activated by this enzyme. A potent carcinogen in tobacco smoke, 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), fitted the template but could not be modelled to form a favourable nitrogen-anion interaction. Experimental substrate competition studies also showed that NNK is unlikely to be a CYP2D6 substrate. It was also shown that the widely used drug for treatment of breast cancer, trans-1-(4-β-dimethylaminoethoxyphenyl)-,2-diphenyl-l-ene (tamoxifen), did not fit the molecular template and is unlikely to be metabolized by CYP2D6. Coordinates of the template are available.

Original languageEnglish
Pages (from-to)2211-2219
Number of pages9
JournalCarcinogenesis
Volume12
Issue number12
DOIs
Publication statusPublished - 1 Dec 1991

Fingerprint Dive into the research topics of 'A three-dimensional molecular template for substrates of human cytochrome P450 involved in debrisoquine 4-hydroxylation'. Together they form a unique fingerprint.

  • Cite this