Towards automated prediction of metabolites and non-substrates of cytochrome P450 2D6 and 3A4 enzymes by protein-ligand docking
| Main Authors: | Hutter, Michael Christopher, Herzinger, Sascha |
|---|---|
| Format: | info publication-workingpaper |
| Bahasa: | eng |
| Terbitan: |
, 2018
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| Subjects: | |
| Online Access: |
https://zenodo.org/record/1421606 |
Daftar Isi:
- CYP2D6 and CYP3A4 are two major enzymes that contribute to the metabolic conversion of xenobiotics. Therefore it is of interest to predict the sites of metabolism in pharmaceutical compounds. Molecular docking was carried out applying AutoDock4.2 to generate a large number of docking poses for 95 ligands comprising substrates as well as non-substrates within structural models of these cytochromes. The obtained conformations were analyzed in a semi-automated way to assign potential hydroxylations, N- and O-dealkylations, as well as oxidation of sulfur, nitrogen, and C=C double bonds. The distance between the iron atom of the cytochrome and the ligand atom found closest in conjunction with the kind of that atom was used to assign potential sites of metabolism. Furthermore, we applied the Wilcoxon-Mann-Whitney test to investigate whether identical distributions of ligand conformations could be obtained by performing substantially fewer docking runs. We found that the vast majority of all docking poses within a range of 3 kcal/mol of the best ranked conformation contain the experimentally observed sites of reactions. On the other hand, also most non-productive conformations are found within this range. The number of required docking runs to obtain highly similar distributions of ligand poses compared to 1000 runs increases drastically with the number of flexible side chains that are included. The unambiguous classification into substrates and non-substrates solely based on the distribution of the type of binding modes is not feasible. Likewise, the amount of false positive matched sites suggests to use docking in combination with ligand-based prediction methods.