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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Comparative Pharmacophore Modeling of Organic Anion Transporting Polypeptides: A Meta-Analysis of Rat Oatp1a1 and Human OATP1B1

Biophysics Program, The Ohio State University, Columbus, Ohio (C.C.); Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (K.S.P.); Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland (C.C., P.W.S., S.E.); and GeneGo, Inc., St. Joseph, Michigan (S.E.)

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.

Address correspondence to: Dr. Sean Ekins, GeneGo Inc., 500 Renaissance Drive, Suite 106, St. Joseph, MI 49085. E-mail sean{at}genego.com

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