2. Human Apical Sodium Dependent Bile Acid Transporter
(ASBT)
The human apical sodium dependent bile acid transporter (ASBT)
is a high efficacy, high capacity transporter expressed on the apical
membrane of intestinal epithelial cells and cholangiocytes.
It assists absorption of bile acids and their analogs, thus providing
an additional intestinal target for improving drug absorption.
Baringhaus and colleagues developed a pharmacophore model
based on a training set of 17 chemically diverse inhibitors of ASBT.
3. The model revealed ASBT transport requirement as one hydrogen
bond donor, one hydrogen bond acceptor, one negative charge, and
three hydrophobic centers.
It is mainly expressed in intestine and kidney, affecting drug
absorption and excretion.
4.
5. Organic Cation Transporter
(OCT)
OCT facilitate the uptake of many cationic drugs across many
different barrier membranes from kidney, liver and intestine
epithelia.
A broad range of drugs or their metabolites fall into the chemical
class of organic cation (carrying a net positive charge at
physiological pH) including Antiarrhythmics, β adrenoreceptor
blocking agents, antihistamines, antiviral agents and skelatal
muscle relaxing agents.
6. Three OCTs have been cloned from different species, OCT1, OCT2
and OCT3.
A human OCT1 pharmacophore model was developed by analyzing
the extent of inhibition of TEA uptake in HeLa cells of 22diverse
molecules.
The model suggest the transport requirements of human OCT1 as three
hydrophobic features and one positive ionizable feature.
Molecular determinants of substrate binding to human OCT2 and
rabbit OCT2 .
Both 2D and 3D QSAR analyses were performed to identify and
discriminate the binding requirements of the two orthologs.
This work illustrates the sensitivity of in silico modeling in
discriminating similar transporters.
7.
8.
9.
10.
11. Organic Anion Transporting Polypeptide
(OATPs)
Influence the plasma concentration of many drugs by actively
transporting them across a diverse range of tissue membranes such
as liver, intestine, lung and brain.
Because of their broad substrate specificity OATPs transport not
only organic anionic drugs as a originally thought but also organic
cationic drugs.
Currently 11 human OATPs have been identified, and the
substrate binding requirements of the best studied OATP1B1 were
successfully modeled with the metapharmacophore approach.
Assessing a training set of 18 diverse molecules, the
metapharmacophore model identified three hydrophobic features
flanked by two hydrogen bond acceptor features to be the essential
requirement for OATP1B1 transport.