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Prediction of pathways of drug metabolism: In silico approaches.
The majority of the work done in the In silico prediction of
drug metabolism has been carried out to investigate cytochrome P450,
or CYP mediated metabolism,
and this will be the major focus of this presentation.
However, other metabolic routes of phase one metabolism,
and also phase two metabolism,
can also be predicted and a number of these will be exemplified.
There have been two major scientific approaches
to the In silico prediction of drug metabolism,
looking at one, the substrate,
and two, the enzyme involved.
The first is based on consideration of the substrate molecule itself.
What are the physical chemical properties of the molecule?
For example, Lipophilicity or electronic structure.
These help to identify potential sites of metabolism.
In conjunction, the construction of
pharmacophore models describe properties of the molecules.
For example, functional atoms or groups,
in three dimensional space,
in the absence of the enzyme.
The second is based on knowledge of the structure of the enzyme itself,
and its mechanism of action.
Having a model structure for the enzyme,
means that the substrate can be docked in the active site,
either manually, or by using docking software.
There are also a number of database
and other computer-based approaches to prediction metabolism,
including metabolic databases, software to predict metabolism,
and methods which use a combination of In silico prediction
and mass spectrametric metabolite identification.
These will be discussed in the second part of the presentation.