3. 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.
4. *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.
6. *P- glycoprotein is an ATP dependent efflux transporter that transports a
broad range of subtrates out of the cell.
*It affects drug disposition by reducing absorption and enhancing renal and
hepatic excretion.
*Pgp is known to limit the intestinal absorption of the anti cancel drug
paclitaxel and restricts the cns penetration of HIV proteaase inhibitors.
*Its is also responsible for multiple drug resistance in cancer chemotherapy.
Because of its significance in drug disposition and effective cancer
treatment,
*So, we can conclude that p-gp attracted numerous efforts and has become
the most extensively studied transporter, with abundant experimental
data.
7. *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 , and ring aromatic features as well as their geometric
arrangement were identified to be the substrate requirement for P-gp.
*Authors derived robust QSAR model that revealed two hydrophobic
features, two hydrogen bond acceptors, and 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.
8. * 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 (Fig. 2)
or allosterically; (ii) interfering with ATP hydrolysis; and (iii)
altering integrity of cell membrane lipids.1,10,17–19 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.19 Many inhibitors (verapamil, cyclosporin A, trans-
flupenthixol, etc.) are themselves transported by P-gp.
10. *Breast cancer resistance protein is another ATP dependent efflux
transporter that confers resistance to a variety of anticancer agents
anthracyclines.
*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.
*Zhang and colleagues generated a BCRP 3DQSAR model by analyzing
structure and activity of 25 flavonoid analogs
*The model anaphasizes very specific structural feature requirements for
BCRP such as the presence of a 2,3-double bond in ring C and hydroxylation
at position 5.
11. *Because the model in only based on a set of closely
related structure instead of diverse set, it should be
applied with caution.
13. *The organic cation transporter facilitate the uptake of many cationic drugs
across different membranes of kidney and intestine.
*A broad range of drugs or their metabolites fall into chemical class of
organic cation including antiarrythmics, B-adrenoaceptor blocking agents,
antihistaminics, antiviral agents.
*These OCTs have been cloned from different species, OCT1/2/3. a human
OCT pharmacophre model was developed.
*2Dand 3D-QSAR analyses were performed to identify and discriminate the
binding requirements of two orthology.
*The same chemical hydrogen bonding feature set the two orthology apart.
*This work illustrates the sensitivity of in silico modeling in discriminating
similar transporters.
15. *Organic anion transporting polypeptides influence the plasma conc of many
drugs by actively transporting them across various tissue membranes such
as liver, intestine, lung and brain.
*OATP transport not only organic anionic drugs but also organic cationic
drugs.
*OATP1B1 were successfully modeled with metapharmacophre approach
recently.
*The model identifies three hydrophobic features flanked by two hydrogen
bond acceptor features to be essential requirement for OATP1B1 transport.
18. *Nuxleoside 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 (CNT1 CNT2 CNT3) and equilibrative nucleoside transporter
(ENT1 ENT2 ENT3)
*Each have different substrate specificity.
*ENT have broad affinity, low selectivity and are ubiquitously located
*CNT have high affinity, selective located in epithelia of intestine kidney, liver and
brain, indicating their involvement in drug disposition, distribution and excretion.
19. *The first 3D-QSAR model for nucleoside transporter was generated back in
1190.
*All models show the common features required for nucleoside transporter-
mediated transport: two hydrophobic features and one hydrogen bond
acceptor on the pentose ring.
*According to researchers results they found that CNT2 is the most selective
transporter whereas ENT1 has broadest inhibitor specificity.
21. *Human peptide transporter is a low affinity high capacity to peptide
transport system that transport a diverse range of substrate including B-
lactam antibiotics and ACE inhibitors.
*It is mainly expresed in intestine and kidney affecting drug absorption and
excretion.
*A pharmacophore model is based on three high affinity substrates(gly-sar,
bestatin, enalapril) were taken
*They recognize two hydrophobic features, one hydrogen bond donor, one
hydrogen bond acceptor, and negative ionizable feature to be hPEPT1
transport requirements.
22. *The pharmacophore model was subsequently applied to screen the CMC
database with over 8000 drug like molecules.
*The anti dibetic 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.
24. *The human apical sodium- dependent bile acid transporter is high efficacy,
high capacity transporter expressed on the apical membrane of intestininal
epithelial cells and cholangiocytes
*It assist absorption of bile acid 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.
25. *The model revealed ASBT transport requirements as one hydrogen bond
donor, one hydrogen bond acceptor, one negative charge, and three
hydrophobic centres.
*These 3D- QSAR model derived from the structure and activity of 30 ASBT
inhibitors and substrate.
27. *The BBB-choline transporter is a native nutrient transporter that transports
choline, a charged cation, across the bbb into the CNS.
*Geldenhuys and colleagues applied a combination of empirical and
theoretical methodologies to study its binding requirements.
*The 3D-QSAr models were built with emperical ki data obtained from in situ
rat brain perfusion experiments with structurally diverse set of compounds.
*Were identified to be important for BBB-choline transporter recognition.
28.
29. *
*Computer application in pharmaceutical research and development, by
Sean Ekins published by john wiley and sons Inc.
*http://crdd.osdd.net/admet.php
*https://en.wikipedia.org/wiki/Active_transport
*https://www.solvobiotech.com/transporters/bcrp
*https://en.wikipedia.org/wiki/Organic-anion-transporting_polypeptide
