Structure‐Based Methods for Predicting the Sites and Products of Metabolism
Chris Oostenbrink · Methods and principles in medicinal chemistry · 2014
An overview is given of computational tools to rationalize and predict the sites of metabolism of substrates, due to catalysis by cytochrome P450 enzymes. The versatility and promiscuity of the enzymes seems to be the result of diverse substrate-protein interactions, an extensive flexibility and malleability of the active site and the possible role of water molecules in the active site. These effects pose serious challenges to the computational tools that are being used, and it appears imperative to include all degrees of freedom of the three actors involved in the binding process: the substrate, the enzyme, and the solvent in which they are embedded. The primary limitations to current day structure-based approaches are not due to limited understanding of the relevant processes or due to a lack of appropriate algorithms to tackle these. Rather, the versatility of the CYPs themselves, which intrinsically follows from their function, requires the most from the available methods and does not allow for any assumptions or approximations that may be valid for more specific targets.