Chemistry Reference
In-Depth Information
adjacent cells (paracellular transport). In addition, molecules that enter
the cytoplasm of epithelial cells can be actively transported back by
specific transporters to the intestinal lumen; this efflux process is mainly
a function of a transporter in the cell membrane called P-glycoprotein
(P-gp) [15].
The field of predicting oral absorption was first defined by the Rule of Five
proposed by Lipinski
et al
. [16]. The Rule of Five established guidelines for the
identification of compounds with possible low absorption and permeability:
1.
molecular weight < 500;
2.
calculated logP < 5 (CLOGP) or Moriguchi logP < 4.15 (MLOGP);
3.
number of hydrogen bond donors (OH and NH groups) < 5;
4.
number of hydrogen bond acceptors (N and O atoms) < 10.
A drawback of the Rule of Five is that it can give only a very limited
classification of molecules. Nowadays, many models for prediction of human
intestinal absorption (HIA) are available, applying a variety of statistical and
machine-learning approaches which include multiple linear regression, nonlinear
regression, partial least square regression, linear discriminant analysis,
classification and regression trees, artificial neural networks (ANNs), genetic
algorithms (GAs), support vector machines (SVMs), so on. Considering that
physicochemical properties are related to intestinal absorption, many
physicochemical descriptors were introduced in the prediction of HIA, such as
polar surface area (PSA), partition coefficients, molecular size, hydrogen bonding
descriptors, topological descriptors, and even quantum chemical descriptors [13].
Molecular descriptors to predict the intestinal absorption or oral bioavailability are
used as variables to generate prediction models. Molecular descriptors can be
divided into three main categories, due to their dependence on the dimensionality
of the structural representation:
