Bioorganic & Medicinal Chemistry 2011-01-01

Elucidation of common pharmacophores from analysis of targeted metabolites transported by the multispecific drug transporter—Organic anion transporter1 (Oat1)

Valentina L. Kouznetsova, Igor F. Tsigelny, Megha A. Nagle, Sanjay K. Nigam, Valentina L. Kouznetsova, Igor F. Tsigelny, Megha A. Nagle, Sanjay K. Nigam

Index: Bioorg. Med. Chem. 19 , 3320-40, (2011)

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Abstract

Organic anion transporter 1 (Oat1), first identified as NKT, is a multispecific transporter responsible for the handling of drugs and toxins in the kidney and choroid plexus, but its normal physiological role appears to be in small molecule metabolite regulation. Metabolites transported by Oat1 and which are altered in the blood and urine of the murine Oat1 knockout, may serve as templates for further drug design. This may lead to better tissue targeting of drugs or design of Oat1 inhibitors that prolong the half-life of current drugs. Due to the multispecificity of the transporter, 19 of known targeted metabolites have different chemical structures and properties that make constructing a common pharmacophore model difficult. Here we propose an approach that clustered the metabolites into four distinct groups which allowed for the construction of a consensus pharmacophore for each cluster. The screening of commercial molecular databases determined the top candidates whose interaction with Oat1 was confirmed in an experimental model of organic anion transport. Thus, these candidate selections represent potential molecules for further drug design.Copyright © 2011 Elsevier Ltd. All rights reserved.