Pharmacophore Estimation and 3D-QSAR of Ligands for Organic Anion Transporting Polypeptide 1B1 (OATP1B1)

Content Provider	Semantic Scholar
Author	Watanabe, Etsuro Yamaotsu, Noriyuki Kusuhara, Hiroyuki Hirono, Shuichi Sugiyama, Yuichi
Copyright Year	2008
Abstract	The liver is one of the most important organs responsible for the elimination of xenobiotics including many kinds of drugs used clinically. It has been shown that transporters are involved in the hepatic uptake of xenobiotics. Among these transporters, we focused on organic anion transporting polypeptide 1B1 (OATP1B1) in this study. OATP1B1 is predominantly expressed in the sinusoidal membrane of liver parenchymal cells (hepatocytes), and mediates cellular uptake of a variety of xenobiotic compounds, particularly amphipathic organic anions. Substrates of OATP1B1 include clinically important anionic drugs, such as HMG-CoA reductase inhibitors (including pravastatin and pitavastatin) and angiotensin II receptor antagonists (including valsartan and olmesartan). In vitro transport studies using cryopreserved human hepatocytes have shown that it makes a significant contribution to the hepatic uptake of such clinically important drugs. For most OATP1B1 substrates, hepatic uptake mediated by OATP1B1 is one of the determining factors of the systemic exposure. Inhibition of OATP1B1 by its inhibitors and genetic polymorphisms/mutations of OATP1B1 resulting in a reduced transport activity produce a significant increase in the systemic exposure of OATP1B1 substrate drugs [1-3]. Therefore, a logical molecular design based on substrate recognition mechanisms of OATP1B1 will facilitate optimization of the pharmacokinetic properties of anionic drugs. In the present study, we investigated the binding conformation of ligands to human OATP1B1and the spatial arrangement of the key functional groups for binding to OATP1B1 (pharmacophore) using in silico ligand-based drug design methods followed by the three dimensional quantitative activity relationship (3D-QSAR) study between ligands and OATP1B1.
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Alternate Webpage(s)	http://bukai.pharm.or.jp/bukai_kozo/yousi/KP226.pdf
Language	English
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Resource Type	Article