ACTIVE TRANSPORT- hPEPT1,ASBT,OCT,OATP, BBB-Choline Transporter.pptx

21-11-2022 © R R INSTITUTIONS , BANGALORE 1
ACTIVE TRANSPORT: hPEPT1 , ASBT, OCT ,
OATP, BBB-CHOLINE TRANSPORTER
RR COLLEGE OF PHARMACY
SUBMITTED BY: SUBMITTED TO:
PAWAN DHAMALA PROF. Mr. K MAHALINGAM
2nd SEM , M.PHARMACY
DEPARTMENT OF PHARMACEUTICS

21-11-2022 © R R INSTITUTIONS , BANGALORE
2
• INTRODUCTION
• ACTIVE TRANSPORT
• HPEPT1
• ASBT
• OCT
• OATP
• BBB-CHOLINE TRANSPORTER

INTRODUCTION
Historically, drug discovery has focused almost exclusively on
efficacy & selectivity against the biological target.
Drug candidates fail at phase 2 & 3 clinical trail because of
undesirable drug PK properties including ADME & toxicity.
To reduce the attrition rate at more expensive later stage, in-vitro
evaluation of ADME properties in the early phase of drug discovery
has widely adopted.
Many high throughput in-vitro ADME & T property screening assay
have developed & applied successfully.
Fueled by ever increasing computational power & significant advance
of in silico modeling algorithms, numerous computational program
that aim at modeling ADMET properties have emerged.

 Transporter should be an integral part of any ADMET modelling
program because of their ubiquitous presence on barrier memberanes
& the substantial overlap between their substrates & many drugs.
 Unfortunately, because of our limited understanding of transporters,
most prediction programs do not have a mechanism to incorporated
the effect of active transport.
 However, interest in these transporters has resulted in a relatively large
amount of in vitro data, which in turn have enabled the generation of
pharmacophore & QSAR models for many of them.
 These models have assisted in the understanding of the complex
effects of transporters on drug disposition, including absorption,
distribution & excretion.
ACTIVE TRANSPORT

A comprehensive list of available commercial ADMET modelling
software has been provided till date.

The human peptide transporter (hPEPT1) is a low-affinity high-capacity
oligopeptide transport system that transports a diverse range of substrates
including β-lactam antibiotics and angiotensin-converting enzyme (ACE)
inhibitors .
It is mainly expressed in intestine and kidney, affecting drug absorption and
excretion.
A pharmacophore model based on three high affinity substrates (Gly-Sar,
bestatin, and enalapril) recognized two hydrophobic features, one hydrogen
bond donor, one hydrogen bond acceptor, and one negative ionizable
feature to be hPEPT1 transport requirements .
hPEPT1

This pharmacophore model was subsequently applied to screen the
CMC database with over 8000 drug like molecules. The antidiabetic
repaglinide and HMG-CoA reductase inhibitor fluvastatin were
suggested by the model and later verified to inhibit hPEPT1 with
submillimolar potency.
This work demonstrated the potential of applying in silico models in
high-throughput database screening.

 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 .
 The model revealed ASBT transport requirements as one hydrogen bond
donor, one hydrogen bond acceptor, one negative charge, and three
hydrophobic centers.
 These requirements are in good agreement with a previous 3D-QSAR
model derived from the structure and activity of 30 ASBT inhibitors and
substrates.
ASBT

The organic cation transporters (OCTs) facilitate the uptake of many
cationic drugs across 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 skeletal muscle-relaxing agents.
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 22 diverse
molecules.
 The model suggests the transport requirements of human OCT1 as
three hydrophobic features and one positive ionizable feature .
OCT

Molecular determinants of substrate binding to human OCT2 and
rabbit OCT2 were recently reported . Both 2D- and 3D-QSAR
analyses were performed to identify and discriminate the binding
requirements of the two orthologs.
The models showed the same chemical features, highlighting their
similarities. However, the orientation of a critical hydrogen bonding
feature set the two orthologs apart. This work illustrates the sensitivity
of in silico modeling in discriminating similar transporters.

OATP
Organic anion transporting polypeptides (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 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 recently .
Through 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.
 Similar requirements were derived from another 3D-QSAR study based
on rat Oatp1a5 . 17

The BBB-choline transporter is a native nutrient transporter that
transports choline, a charged cation, across the BBB into the CNS .
Its active transport assists the BBB penetration of choline like
compounds, and understanding its structural requirements should
afford a more accurate prediction of BBB permeation.
Even though the BBB-choline transporter has not been cloned,
Geldenhuys and colleagues applied a combination of empirical and
theoretical methodologies to study its binding requirements .
The 3DQSAR models were built with empirical Ki data obtained from
in situ rat brain perfusion experiments with a structurally diverse set
of compounds.
20
BBB-Choline Transporter

Three hydrophobic interactions and one hydrogen bonding interaction
surrounding the positively charged ammonium moiety were identified
to be important for BBB-choline transporter recognition.
Even though the model statistical significance is not optimal (q2 <
0.5), it does provide a useful estimation of BBB-choline transporter
binding requirements.
More accurate in silico models could be generated once higher-quality
data from the cloned BBB-choline transporter are available.

• Computer Applications in Pharmaceutical Research & Development
by Sean Ekins
• www.slideshare.com
• www.google.com
• www.youtube.com

ACTIVE TRANSPORT- hPEPT1,ASBT,OCT,OATP, BBB-Choline Transporter.pptx

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