Poster Presenter

CYP2D6 Pharmacogenetics And Dextromethorphan Metabolism: A Molecular Modelling Study
Shah IM, Wittayanarakul K., Breslin CJ, Mackay SP
UK

Introduction: Dextromethorphan is used as a probe drug and O-demethylated by cytochrome 2D6 (CYP2D6) to dextrorphan. The metabolite concentration can be quantified in the urine and used to assess patients CYP2D6 phenotype status. Both in vitro and clinical studies have demonstrated that the CYP2D6*17 allelic variant produces lower quantities of dextrorphan (1, 2). To investigate this pharmacogenetic variability, we have used molecular docking studies to analyse the interaction of dextromethorphan with the active site of wild-type and CYP2D6*17 enzyme structures.

Methods: The crystal structure of CYP2D6 (PDB ID: 2F9Q) was used for in silico generation of CYP2D6*17 structure (T107I, R296C and S486T). The Gaussian 03 program was used to optimise the structure of dextromethorphan. AutoDock4 was used to calculate the binding free energy of dextromethorphan with the active site of the wild-type and mutant enzyme structures.

Results: The docking results show that the free energy of binding of dextromethorphan with CYP2D6 is -7.2 kcal/mol which is more favourable than CYP2D6*17 (–4.7 kcal/mol). This correlates with the reduced substrate affinity (increased Km) of CYP2D6*17 and the intermediate metaboliser phenotype associated with this mutated enzyme compared to wild-type (1).

Discussion: Our results suggest that the higher free energy of binding of dextromethorphan with CYP2D6*17 is related to the altered active site conformation caused by the triple amino acid mutation. This may explain the reduced metabolic activity of this enzyme variant and we plan to explore this further using molecular dynamics simulations.

(1) Shen H. et al. Drug Metab Dispos. 2007; 35(8): 1292-1300.

(2) Wennerholm A. et al. Clin Pharmacol Ther. 2002; 71(1): 77-88.