MetaSite
MetaSite is a computational procedure that predicts metabolic transformations related to cytochrome-mediated reactions in phase I metabolism. Validation of the method 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 85% 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.
MetaSite is the only software developed using 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).
Key Features
- predict "hot spots" in the molecule to help chemists focus their design of compounds to reduce CYP mediated metabolism.
- suggest the regions that contribute most towards each "hot spot", providing additional derivation sites for chemists to design new stable compounds.
- 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.
- warn about the potential of CYP mechanism-based inhibition, one of the major metabolic hurdles in the development of new safer drugs.
References
- Cruciani G, Carosati E, De Boeck B, Ethirajulu K, Mackie C, Howe T, Vianello R. J Med Chem., 2005 Nov 3;48(22):6970-9.
- Zhou D, Afzelius L, Grimm SW, Andersson TB, Zauhar RJ, Zamora I. Drug Metab Dispos., 2006 Jun; 34(6):976-83.
- Ahlström MM, Ridderström M, Zamora I, Luthman K. J Med Chem., 2007 Sep 6;50(18):4444-52.