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Methadone is a morphine-substitute drug in methadone maintenance treatment (MMT) program to treat patients with opioid dependency. However, the methadone clinical effects are depending on the methadone metabolism rates that vary among the patients with genetic polymorphism of cytochrome P450s (CYPs). Our previous study showed methadone has different binding affinity due to the polymorphisms in CYP2B6, CYP2D6 and CYP3A4 that could contribute to the methadone metabolism rate. In this work, the conformation and interactions of  R - and  S -methadone in wild type CYP2B6, CYP2D6 and CYP3A4 were further studied in order to understand behaviour of  R - and  S -methadone at the CYP binding site. Clustering analysis showed that the conformation of  R - and  S -methadone in CYP2B6 are most stable, thus could lead to a higher efficiency of methadone metabolism. The conformation fluctuation of methadone in CYP2D6 could due to relatively smaller binding pocket compared with CYP2B6 and CYP3A4. The binding sites volumes of the studied CYPs were also found to be increased upon the binding with methadone. Therefore, this might contributed to the interactions of both  R - and  S -methadone in CYPs were mainly by hydrophobic contacts, van der Waals and electrostatic interactions. In the future, should an inhibitor for CYP is to be designed to prolong the prolonged opioid effect, the inhibitor should cater for single CYP isozyme as this study observed the behavioural differences of methadone in CYP isozymes.

Conformations and interactions comparison between R - and S -methadone in wild type CYP2B6, 2D6 and 3A4