Chemistry Reference
In-Depth Information
there is not a general methodology for the computer prediction of absorption
properties.
COMPUTATIONAL APPROACHES IN METABOLISM
Most of drug discovery projects are faced with stability limitations in developed
series of compounds causing new drugs to be dismissed. Many pharmacologically
interesting molecules are passed over because they are not stable enough. These
issues have contributed to the development of new strategies for structural
modifications focusing in improved stability of future promising compounds [10].
In order to accelerate the development of active compounds, metabolic
considerations were integrated into drug design and lead-optimization strategies,
comprising the evaluation of chemistry and biochemistry metabolic reactions and
their role in the activation/deactivation process. The efficiency of these processes
can be improved by
in silico
methods in order to provide reliable and versatile
metabolic predictions [23].
Cellular metabolism is characterized as an interlaced network of interactions
involving several levels of regulation. This system has a very complex behavior
and thus cannot be predicted with only an intuitive approach. However,
mathematical models of cellular metabolism are able to create an appropriate
framework to represent and investigate different stages of metabolism [24-26].
The statistical methods used to search correlations include multiple linear
regression analysis, multivariate analysis, and unsupervised machine-learning
approaches, neural networks and genetic algorithms. Thus, a computational
approach adopts a hierarchy of descriptions involving different levels of detailed
and precise information [23, 27].
The most important enzymes involved in human metabolism are the cytochrome
P450. Despite the fact that 57 active genes for CYP are known, only a few
enzymes with different prevalence in the human liver are directly related to
metabolism. The cytochrome P450 enzymes are a superfamily of heme-
thiolateproteins responsible for catalyzing the oxidation of many endogenous and
foreign substrates in the body. Danielson and coworkers estimated that 75% of all
drugs are metabolized by cytochrome P450 enzymes, highlighting the importance
