Background: The metabolic action of CYP2D6 remains a crucial factor influencing the therapeutic
outcomes for many drug molecules while others are either only slightly affected or not affected
Objective: This study seeks to understand, atomistic resolution, the structural and physicochemical factors
influencing CYP2D6 metabolic discrimination.
Method: Explicit solvent molecular dynamics simulations in GROMACS were employed to probe the
conformational dynamics of CYP2D6 following which the most populated structures were employed for
ligand interaction docking studies with AutoDock Vina using selected CYP2D6 drug substrates.
Results: Using atomistic treatment at the molecular mechanics level and multiple CYP2D6 conformations
for docking, two primary ligand binding subsites (subsites A and B) were identified within an
otherwise extensive ligand recognition site. The studied drug molecules were found to display distinct
preference for either of the two subsites. Correlation and center-of-mass distribution analysis showed
subsite binding preference to depend significantly on CYP2D6 conformation, as well as molecular
properties such as molecular size and number of hydrogen bond donor present in the drug molecule.
Conclusion: CYP2D6 binding subsite A was found to be relatively selective for small molecular weight
with higher polarity compared with subsite B which tends to favor larger molecular weight and relatively
hydrophobic molecules such as tamoxifen and imipramine. Our simulations further suggest that the
ability of the CYP2D6 binding site residues to sample different conformations may partly account for
its ability to metabolize diverse drug classes.