Hydrogen Bonding in Human P450-Substrate Interactions: A Major Contribution to Binding Affinity

Abstract

The importance of hydrogen bonding, a relatively strong intermolecular force of attraction between molecules in biological systems, is discussed in the respect of P450 substrate affinity towards one or more of the human P450 enzymes that are generally associated with drug and other xenobiotic metabolism. It is shown that calculation of hydrogen bond distances and energies based on simple empirical relationships provide values that agree closely with experimental findings. It is thus possible to estimate the hydrogen bond contribution to P450 enzyme-substrate binding affinity based on modelled interactions and by use of these relatively simple formulae, particularly when employed in conjunction with substrate-lipophilicity relationships.