Elucidation of common pharmacophores from analysis of targeted metabolites transported by the multispecific drug transporter-Organic anion transporter1 (Oat1)
Elucidation of common pharmacophores from analysis of targeted metabolites transported by the multispecific drug transporter-Organic anion transporter1 (Oat1)
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DOI：
10.1016/j.bmc.2011.04.045
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发表时间：
2011-06-01
影响因子：
3.5
通讯作者：
Nigam, Sanjay K.
中科院分区：
文献类型：
--
作者：
Kouznetsova, Valentina L.;Tsigelny, Igor F.;Nigam, Sanjay K.
有机阴离子转运蛋白1（Oat 1），首先被鉴定为NKT，是一种多特异性转运蛋白，负责处理肾脏和脉络丛中的药物和毒素，但其正常生理作用似乎是在小分子代谢物调节中。由Oat1转运的代谢产物，在Oat1敲除小鼠的血液和尿液中发生改变，可以作为进一步药物设计的模板。这可能会导致更好的药物组织靶向或设计Oat 1抑制剂，延长目前药物的半衰期。由于转运蛋白的多特异性，19种已知的靶向代谢物具有不同的化学结构和性质，这使得构建共同的药效团模型变得困难。在这里，我们提出了一种方法，聚类的代谢产物分为四个不同的组，允许为每个集群的共识药效团的建设。商业分子数据库的筛选确定了最佳候选人，其与燕麦1的相互作用在有机阴离子转运的实验模型中得到证实。因此，这些候选选择代表了用于进一步药物设计的潜在分子。(C)2011爱思唯尔有限公司版权所有。
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. (C) 2011 Elsevier Ltd. All rights reserved.