Impact of plasticity and flexibility on docking results for cytochrome P450 2D6: a combined approach of molecular dynamics and ligand docking.

Cytochrome P450s (CYPs) exhibit a large plasticity and flexibility in the active site allowing for the binding of a large variety of substrates. The impact of plasticity and flexibility on ligand binding is investigated by docking 65 known CYP2D6 substrates to an ensemble of 2500 protein structures. The ensemble was generated by molecular dynamics simulations of CYP2D6 in complex with five representative substrates. The effect of induced fit, the conformation of Phe483, and thermal motion on the accuracy of site of metabolism (SOM) predictions is analyzed. For future predictions, the three most essential CYP2D6 structures were selected which are suitable for different kinds of ligands. We have developed a binary decision tree to decide which protein structure to dock the ligand into, such that each ligand needs to be docked only once, leading to successful SOM prediction in 80% of the substrates.