SoM Calculation
Interaction & reactivity
The enzyme super family of P450 cytochromes provides some of the most sophisticated catalysts of drug biotransformation reactions. These enzymes catalyze a wide variety of oxidative and reductive reactions and demonstrate activity on a chemically diverse variety of substrates. Moreover, a small subset of the CYP enzymes is responsible for most drug-metabolizing reactions.
Several aspects of these enzymes, such as the rate and site of metabolism, inhibition, induction, and the selectivity of the various isoforms, are relevant in the lead optimization process during the discovery of new therapeutic agents.
Although there is a large amount of information on the functional role of these enzymes, knowledge of their dynamic motion is still lacking. In-vitro screens for inhibition and metabolic stability can provide some of the information required in drug discovery. The experimental elucidation of the site of metabolism is usually a highly resource-demanding task, requiring several experimental techniques and consuming a considerable amount of compound. Nevertheless, the recognition of the site of metabolism is a great help in designing new compounds with improved pharmacokinetic profiles and in avoiding the presence of toxic metabolites by chemically protecting the metabolic labile moieties in the drug candidate. Another use of metabolism site prediction is in designing pro-drugs where the compound needs to be metabolized in order to become active.
Using the 3D structure of a compound, MetaSite is a computational procedure specifically designed to predict the site of metabolism of xenobiotics and the derived metabolites.
The MetaSite procedure is completely automated, easy to apply, and does not require user assistance. All of the work can be submitted and handled using a batch queue to process large numbers of molecules more easily. MetaSite uses GRID-based representations of the CYP enzymes that have been pre-computed and are stored within the software. The calculations of charges and reactivities, pharmacophoric recognition, descriptor handling, and similarity computation are carried out automatically once the 3D structure of the compounds has been provided. Figure 3-1 shows a schematic representation of the MetaSite workflow.
