Active transporter
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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.
Active transporter
- 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
- 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.
- 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.