This document discusses various drug transporters and how computational models have been used to better understand them. It summarizes that P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are ATP-dependent efflux transporters that impact drug absorption and resistance. The document then reviews pharmacophore and QSAR models developed for these transporters to predict substrate and inhibitor requirements. Finally, it discusses nucleoside transporters and similar computational models generated to understand these transporters and their role in drug disposition.

1. SAKSHI R. YADAV
M.PHARM PHARMACEUTICS
II SEMESTER
SKBCOP,KAMPTEE

2. CONTENTS
• INTRODUCTION
• P-gp
• BCRP
• NUCLEOSIDE TRANSPORTERS

3. INTRODUCTION
• Active transport is the movement of
molecules across a membrane from a
region of their lower concentration to a
region of their higher concentration—
against the concentration gradient.
• Molecules move against the concentration
gradient (low to high).
• Energy must be provided.
• Exhibit saturation kinetics.

4. • Active transport is divided into two types
according to the source of the energy used
to cause the transport:
PRIMARY ACTIVE
TRANSPORT
SECONDARY ACTIVE
TRANSPORT
 They use the energy directly from
the hydrolysis of ATP.
• Sodium potassium Pump
• Calcium pump
• Hydrogen Potassium pump
• Hydrogen / Proton pump
 Energy utilized in the transport of
one substance helps in the
movement of the other substance.
 Energy is derived secondarily,
from energy that has been stored in
the form of ionic concentration
differences of secondary molecular
or ionic substances between the
two sides of a cell membrane,
 created originally by primary
active transport.

5.  Transporters should be an integral part of any ADMET
modeling program because of their ubiquitous presence on
barrier membranes the substantial overlap between their
substance many drugs.
 Unfortunately, because of our limited understanding of
transporters, most prediction programs do not have
mechanism to incorporate 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 and QSAR
models for many of the.

6. • These models have assisted in the understanding of the
mode complex effects of transporters on drug disposition,
including absorption, distribution and excretion.
• Their incorporation into current modeling programs would
also result in more accurate prediction of drug disposition
behavior.
Primary active transport Secondary
active transport

7. P-GlycoProtein
transPorter

8. • P- glycoprotein is an ATP dependent efflux transporter that transports
a broad range of substrates out of the cell.
• It affects drug disposition by reducing absorption and enhancing renal
and hepatic excretion.
• P-gp is known to limit the intestinal absorption of the anti cancel drug
paclitaxel and restricts the CNS penetration of HIV protease
inhibitors.
• Its is also responsible for multiple drug resistance in cancer
chemotherapy. Because of its significance in drug disposition and
effective cancer treatment.
• Ekins and colleagues generated five computational
pharmacophore models
:- to predict the inhibition of P-gp from in vitro on a diverse set of
inhibition with several cell system .
• By comapring and merging all P-gp pharmacophore models, common
areas of identical chemical features such as
 hydrophobes,
 hydrogen bond acceptor
 ring aromatic features as well as their geometric arrangement were
identified to be the substrate requirement for P-gp.

9. • Cianchetta and colleagues combined allignment 3D description
and physiochemical desription to model inhibition of Calcein
accumulation in caco-2-cells.
• Authors derived robust QSAR model that revealed
 two hydrophobic features
 two hydrogen bond acceptors
 the molecular dimension to be essential determinants of P-gp
mediated transport
• These identified transport requirements not only to help screen
compounds with potential reflux related bioavailability problems,
but also to assist the identification of P-gp inhibitors.
• A recent pharmacophore based database screening has proposed 28
novel P-gp inhibitors from the Derwent World Drug Index.

10. • Inhibition of P-gp:-
The inhibition of efflux pump is mainly done in order to improve the
delivery of therapeutic agents. In general, P-gp can be inhibited by three
mechanisms:
(i) blocking drug binding site either competitively, non-competitively or
allosterically;
(ii) interfering with ATP hydrolysis; and
(iii)altering integrity of cell membrane lipids.
 The goal is to achieve improved drug bioavailability, uptake of drug in
the targeted organ, and more efficacious cancer chemotherapy through
the ability to selectively block the action of P-gp.
 Inhibitors are as structurally diverse as substrates.Many inhibitors
(verapamil, cyclosporin A, trans-flupenthixol, etc.) are themselves
transported by P-gp.

11. BCRP

12. • Breast cancer resistance protein is another ATP dependent efflux
transporter that confers resistance to a variety of anticancer agents
including anthracyclines and mitoxantrane.
• In addition to high level of expression in hematological malignancies
and solid tumors, BCRP is also expressed in intestine, liver and brain
thus implicating its very complicated role in drug disposition
behavior.

13. • Zhang and colleagues generated a BCRP 3D-QSAR model by
analyzing structure and activity of 25 flavonoid analogues.
• The model emphasizes very specific structural feature requirements
for BCRP such as
 the presence of a 2,3-double bond in ring C
 hydroxylation at position 5.
• The caveat should be considered for all predictive in silico models,
because no model can cover all possible chemical space.

14. NuCleoside TRaNsPoRTeR

15. • Nucleoside transporters transport both
 naturally occurring nucleoside and
 synthetic nucleoside analogs
that are used as anticancer drugs anti viral drugs.
• There are various types of nucleoside transporter, including
Concentrative nucleoside
transporter
Equilibrative nucleoside
transporter
(CNT1, CNT2 ,CNT3) (ENT1, ENT2, ENT3)
 ENT’s have
 broad affinity,
 low selectivity and
 are ubiquitously located
 CNT’s have
 high affinity,
 selective located in epithelia of
intestine kidney, liver and brain,
indicating their involvement in
drug disposition, distribution and
excretion.

16. • The first 3D-QSAR model for nucleoside transporter was generated
back in 1990.
• A more comprehensive study generated disintive model for
CNT1,CNT2 & ENT1 with both pharmacophore & 3D-QSAR
modeling techniques.
• All models show the common features required for nucleoside
transporter-mediated transport:
 two hydrophobic features and
 one hydrogen bond acceptor on the pentose ring.
• The modeling results also support the previous observation that CNT2
is the most selective transporter wherease ENT1 has broadest
inhibitoring specificity.
• 3D-QSAR model for CNT3 by assessing the transport activity of 33
Nucleoside analogues.