COMPUTER AIDED DRUG DEVELOPMENT

ASBT
OCT
OATP
BBB CHOLINE TRANSPOR

1. Presented by MISS. JYOTI DIPAK MHOPREKAR M Pharmacy (First Year, Sem Ii) Roll No. 06 DEPARTMENT OF PHARMACEUTICS SHREE SANTKRUPA COLLEGE OF PHARMACY GHOGAON . ASBT, OCT, OATP, BBB Choline transporetr

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. 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.

5. 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.

6. 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.

7. Thank you