Computational predictions of the site of metabolism of cytochrome P450 2D6 substrates: Comparative analysis, molecular docking, bioactivation and toxicological implications

Kevin A. Ford, Gregory Alexander Ryslik, Jasleen Sodhi, Jason Halladay, Dolo Diaz, Donna Dambach, Melisa Masuda

Research output: Contribution to journalReview article

5 Citations (Scopus)

Abstract

Cytochrome P450 2D6 (CYP2D6) is a polymorphic enzyme responsible for metabolizing approximately 25% of all drugs. CYP2D6 is highly expressed in the brain and plays a role as the major CYP in the metabolism of numerous brain-penetrant drugs, including antipsychotics and antidepressants. CYP2D6 activity and inhibition have been associated with numerous undesirable effects in patients, such as bioactivation, drug-associated suicidality and prolongation of the QTc interval. Several in silico tools have been developed in recent years to assist safety assessment scientists in predicting the structural identity of CYP2D6-derived metabolites. The first goal of this study was to perform a comparative evaluation on the ability of four commonly used in silico tools (MetaSite, StarDrop, SMARTCyp and RS-WebPredictor) to correctly predict the CYP2D6-derived site of metabolism (SOM) for 141 compounds, including 10 derived from the Genentech small molecule library. The second goal was to evaluate if a bioactivation prediction model, based on an indicator of chemical reactivity (ELUMO-EHOMO) and electrostatic potential, could correctly predict five representative compounds known to be bioactivated by CYP2D6. Such a model would be of great utility in safety assessment since unforeseen toxicities of CYP2D6 substrates may in part be due to bioactivation mechanisms. The third and final goal was to investigate whether molecular docking, using the crystal structure of human CYP2D6, had the potential to compliment or improve the results obtained from the four SOM in silico programs.

Original languageEnglish (US)
Pages (from-to)291-319
Number of pages29
JournalDrug Metabolism Reviews
Volume47
Issue number3
DOIs
StatePublished - Jul 3 2015

Fingerprint

Molecular Docking Simulation
Cytochrome P-450 CYP2D6
Toxicology
Computer Simulation
Small Molecule Libraries
Safety
Brain
Static Electricity
Pharmaceutical Preparations
Antidepressive Agents
Antipsychotic Agents

All Science Journal Classification (ASJC) codes

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Pharmacology (medical)

Cite this

Ford, Kevin A. ; Ryslik, Gregory Alexander ; Sodhi, Jasleen ; Halladay, Jason ; Diaz, Dolo ; Dambach, Donna ; Masuda, Melisa. / Computational predictions of the site of metabolism of cytochrome P450 2D6 substrates : Comparative analysis, molecular docking, bioactivation and toxicological implications. In: Drug Metabolism Reviews. 2015 ; Vol. 47, No. 3. pp. 291-319.
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Computational predictions of the site of metabolism of cytochrome P450 2D6 substrates : Comparative analysis, molecular docking, bioactivation and toxicological implications. / Ford, Kevin A.; Ryslik, Gregory Alexander; Sodhi, Jasleen; Halladay, Jason; Diaz, Dolo; Dambach, Donna; Masuda, Melisa.

In: Drug Metabolism Reviews, Vol. 47, No. 3, 03.07.2015, p. 291-319.

Research output: Contribution to journalReview article

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AU - Ford, Kevin A.

AU - Ryslik, Gregory Alexander

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AU - Halladay, Jason

AU - Diaz, Dolo

AU - Dambach, Donna

AU - Masuda, Melisa

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