MetaSite

MetaSite is a computational procedure that predicts metabolic transformations related to cytochrome-mediated reactions in phase I metabolism. MetaSite algorithm is unique being the only software not training set dependent.

MetaSite consider both enzyme-substrate recognition, which is a thermodynamic factor, and the chemical transformations induced by the enzyme, which is a kinetic factor.

MetaSite flowchart was recently improved by experimental information from the Human CYP Consortium Initiative, a joint venture between pharmaceutical companies and Molecular Discovery, working together to solve the most important issues in drug metabolism (for further information on CYP Consortium Initiative, see this page). MetaSite 4.0 gives unprecedented prediction performance. New features include the automatic suggestion of fragment modification to optimize specific metabolic issues (MetaDesign), and an interaction map of the substrate with the P450 cavity (32D) to aid optimisation in the context of the enzyme.

Validation of MetaSite in CYP-Consortium data and in more than forty pharmaceutical companies has shown that the primary site of metabolism was found within the top three MetaSite predictions for more than 90% of the cases.

In addition, MetaSite provides the structure of the metabolites formed with a ranking derived from the site of metabolism predictions. The method also highlights the molecular moieties that help to direct the molecule in the cytochrome cavity such that the site of metabolism is in proximity to the catalytic centre.

Directly blocking the primary site of metabolism can risk creating an inhibitor of the cytochrome, or may negatively affect the activity or selectivity of the compound towards its therapeutic target. Modifying these contributing moieties that most influence the site of metabolism can bypass both of these potential problems.

MetaDesign module available, download pre-computed database fragments here. Uncompress the downloaded files and select them when using the MetaDesign module.

MetaSite screenshots

Key Features

  1. predict "hot spots" in the molecule to help chemists focus their design of compounds to reduce CYP mediated metabolism.
  2. suggest the regions that contribute most towards each "hot spot", providing additional derivation sites for chemists to design new stable compounds.
  3. predict the structures of the most likely metabolites, with exact mass and relative retention time to help and complement the experimental elucidation of metabolite structures.
  4. warn about the potential of CYP mechanism-based inhibition, one of the major metabolic hurdles in the development of new safer drugs.
  5. Produce Phase I and Phase II metabolite structures to be automatically used in MassMetaSite software

New Features (v4.1)

  1. Scan and signal filtering parameters made available to the user.
  2. SoM validation.
  3. 32D amino-acid tags made moveable by the users.

References

Latest versions

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