PT  - JOURNAL ARTICLE
AU  - Cheng Chang
AU  - K. Sandy Pang
AU  - Peter W. Swaan
AU  - Sean Ekins
TI  - Comparative Pharmacophore Modeling of Organic Anion Transporting Polypeptides: A Meta-Analysis of Rat Oatp1a1 and Human OATP1B1
AID  - 10.1124/jpet.104.082370
DP  - 2005 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 533--541
VI  - 314
IP  - 2
4099  - http://jpet.aspetjournals.org/content/314/2/533.short
4100  - http://jpet.aspetjournals.org/content/314/2/533.full
SO  - J Pharmacol Exp Ther2005 Aug 01; 314
AB  - The organic anion transporting polypeptides OATPs are key membrane transporters for which crystal structures are not currently available. They transport a diverse array of xenobiotics and are expressed at the interface of hepatocytes, renal tubular cells, enterocytes, and the choroid plexus. To aid the understanding of the key molecular features for substrate-transporter interactions, pharmacophore models were produced for the two OATPs that have been most extensively studied, namely rat Oatp1a1 and human OATP1B1. Literature data from Chinese hamster ovary, HeLa, human embryonic kidney 293 cells, and Xenopus laevis oocytes were used to construct pharmacophores for each individual transporter which were later merged to show similarities across cell lines for the same transporter. Additionally, meta-pharmacophores were generated from the combined datasets of each cell system used with the same transporter. The pharmacophores for each transporter consisted of hydrogen bond acceptor and hydrophobic features. There was good agreement between the merged and meta-pharmacophores containing two hydrogen bond acceptors and two or three hydrophobic features for Oatp1a1 and OATP1B1. External test sets were used to validate the individual pharmacophores. The meta-pharmacophores were also used to make predictions for molecules not included in the models and provided new molecular insight into the key features for these OATP transporters. This approach can be extended to other transporters for which limited data are available. The American Society for Pharmacology and Experimental Therapeutics