A new sophisticated algorithm
The computational algorithm in MetaSite 7.0 is highly sophisticated and uses simulations to replicate how human metabolic enzymes interact with xenobiotic compounds. For the newly introduced enzymes, exposure and reactivity concepts remain crucial for determining whether a molecule is a potential substrate. However, the prediction does not rely on the classical equation used for CYPs. Instead, it uses the concept of reactivity to select reactive atoms for each enzyme based on the molecule’s structure and the enzyme’s reaction mechanism.
Using the enzyme’s 3D structure (either X-ray or modeled), MetaSite 7 evaluates the exposure of the reactive atom to the enzyme’s cofactor or catalytic residues in the binding site. The algorithm employs the GRID force field to calculate flexible interaction fields (flexible MIFs) between the active site amino acids and the potential substrate. This flexible coupling generates multiple docking poses, which are evaluated by the GRID force field using functions that sum energy contributions such as van der Waals forces, hydrogen bonding, hydrophobic interactions, electrostatic forces, entropic contributions, and steric effects. The resulting poses are ranked by total energy interaction value, and the best pose is chosen and normalized to produce a probability score.
The method is designed and automated so that the user can easily design or import the 2D structure of the potential substrate and customize the list of enzymes for prediction according to their needs.