Chemistry Reference
In-Depth Information
of potential metabolism sites prediction. This is highly advantageous if performed
early in the new drug development process.
In silico
modeling of metabolism
properties can be performed using many different approaches. However, the
metabolism properties are difficult to predict due to multiple physiological
processes resulting from the intestinal absorption and metabolic stability [28-31].
The early prediction of ADME properties is strategic since it increases the success
rate of compounds reaching the pharmaceutical market. In general the programs
perform a comparison of methods (based on pattern recognition) to identify
possible correlations between molecular descriptors and ADME properties,
structural models based on classical molecular mechanics and quantum
mechanical techniques for modeling chemical reactions [32].
In addition to cytochrome P450, other drug metabolizing enzymes and carriers
play an important role in drug-drug interactions. According to Boulenc and
Barberan [33] there is a growing appreciation for the ratio of transport proteins
and drug-drug interactions.
There is a diverse number of softwares used to predict metabolism. Among those
commonly used are Meteor [23], MetabolExpert [34], MetaSite [5].
Meteor is a software-based rule, many of these empirical. Their algorithm
involves three steps. First, the program examines the lead compound and verifies
the existence of variable substructures related to any one of biotransformations
contained in its database. Second, through pre-established rules, Meteor assesses
the chance of biotransformation, based on five levels that are dependent on the
molecule's analyzed logP: probable, plausible, equivocal, doubtful and unlikely
[35]. Finally, a score of biotransformations that may occur concomitantly in the
same compound are performed. The result of this score is based on a set of
established rules, for example, chemical properties inherent in each molecule and
functional group's specific features [36].
The software MetaSite (Fig.
1
) predicts metabolic transformations related to
cytochrome-mediated reactions in phase 1 metabolism, which encompasses
modification of the molecular structure itself, such as oxidation or dealkylation.
