Role of water in molecular docking simulations of cytochrome P450 2D6

Active-site water molecules form an important component in biological systems, facilitating promiscuous binding or an increase in specificity and affinity. Taking water molecules into account in computational approaches to drug design or site-of-metabolism predictions is currently far from straightforward. In this study, the effects of including water molecules in molecular docking simulations of the important metabolic enzyme cytochrome P450 2D6 are investigated. The structure and dynamics of water molecules that are present in the active site simultaneously with a selected substrate are described, and based on this description, water molecules are selected to be included in docking experiments into multiple protein conformations. Apart from the parent substrate, 11 similar and 53 dissimilar substrates are included to investigate the transferability of active-site hydration sites between substrates. The role of water molecules appears to be highly dependent on the protein conformation and the substrate.