Predicting sites of cytochrome P450-mediated hydroxylation applied to CYP3A4 and hexabromocyclododecane

Abstract

This article describes a simple and quick in silico method for the prediction of cytochrome P450 (CYP)-mediated hydroxylation of drug-like compounds. Testosterone and progesterone, two known substrates of CYP3A4, are used to test the method. Further, we apply the procedure to predict sites of hydroxylation of isomers of the flame retardant hexabromocyclododecane by CYP3A4. Within the method, the compound is rotated in the binding pocket of the cytochrome, so that each hydrogen under consideration is placed near the active centre. Afterwards, short molecular dynamics simulations are provided for each step of the rotation. All steps of the simulation are compared concerning the distances between the hydrogens and the active centre and the corresponding energies. The computational results correlate well with experimental results.

Keywords::

• predicting sites of metabolism
• cytochrome P450
• hydroxylation
• metabolism of HBCD

Acknowledgements

This work was financially supported by the cooperation between BAM and ZIB on joint research and development in the field of scientific computing (2010). The authors are indebted to Prof. Hwanseo Park (Seoul National University, Seoul, South Korea) for the kind provision of force field parameters for the haeme-thiolate group and its dioxygen adduct.

Notes

^1. Current address: Department Safety in the Food Chain, Unit Product Identity and Traceability, BfR Federal Institute for Risk Assessment, Berlin, Germany.