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Identification of Thienopyrimidine Scaffold as an Inhibitor of the ABC Transport Protein ABCC1 (MRP1) and Related Transporters Using a Combined Virtual Screening Approach.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-04-30 , DOI: 10.1021/acs.jmedchem.8b01821 Katja Silbermann 1 , Sven Marcel Stefan 1 , Randa Elshawadfy 1 , Vigneshwaran Namasivayam 1 , Michael Wiese 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-04-30 , DOI: 10.1021/acs.jmedchem.8b01821 Katja Silbermann 1 , Sven Marcel Stefan 1 , Randa Elshawadfy 1 , Vigneshwaran Namasivayam 1 , Michael Wiese 1
Affiliation
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A virtual screening protocol with combination of similarity search and pharmacophore modeling was applied to virtually screen a large compound library to gain new scaffolds regarding ABCC1 inhibition. Biological investigation of promising candidates revealed four compounds as ABCC1 inhibitors, three of them with scaffolds not associated with ABCC1 inhibition until now. The best hit molecule-a thienopyrimidine-was a moderately potent, competitive inhibitor of the ABCC1-mediated transport of calcein AM which also sensitized ABCC1-overexpressing cells toward daunorubicin. Further evaluation showed that it was a moderately potent, competitive inhibitor of the ABCB1-mediated transport of calcein AM, and noncompetitive inhibitor of the ABCG2-mediated pheophorbide A transport. In addition, the thienopyrimidine could also sensitize ABCB1- as well as ABCG2-overexpressing cells toward daunorubicin and SN-38, respectively, in concentration ranges that qualified it as one of the ten best triple ABCC1/ABCB1/ABCG2 inhibitors in the literature. Besides, three more new multitarget inhibitors were identified by this virtual screening approach.
中文翻译：
使用组合虚拟筛选方法鉴定Thienopyrimidine支架作为ABC转运蛋白ABCC1（MRP1）和相关转运蛋白的抑制剂。
将具有相似性搜索和药效团建模相结合的虚拟筛选方案应用于虚拟筛选大型化合物库，以获得有关ABCC1抑制的新支架。对有前途的候选物的生物学研究表明，有四种化合物是ABCC1抑制剂，其中三种具有迄今为止尚未与ABCC1抑制作用相关的支架。命中率最高的分子-噻吩并嘧啶-是ABCC1介导的钙黄绿素AM转运的中等效力，竞争性抑制剂，它也使过表达ABCC1的细胞对柔红霉素敏感。进一步的评估表明，它是ABCB1介导的钙黄绿素AM转运的中度有效竞争性抑制剂，是ABCG2介导的脱镁叶绿素A转运的非竞争性抑制剂。此外，硫代嘧啶还可以使ABCB1和ABCG2过表达的细胞分别对柔红霉素和SN-38敏感，其浓度范围使其成为文献中十种最佳的三重ABCC1 / ABCB1 / ABCG2抑制剂之一。此外，通过这种虚拟筛选方法还鉴定出了另外三种新的多靶点抑制剂。
更新日期：2019-03-29
中文翻译：
使用组合虚拟筛选方法鉴定Thienopyrimidine支架作为ABC转运蛋白ABCC1（MRP1）和相关转运蛋白的抑制剂。
将具有相似性搜索和药效团建模相结合的虚拟筛选方案应用于虚拟筛选大型化合物库，以获得有关ABCC1抑制的新支架。对有前途的候选物的生物学研究表明，有四种化合物是ABCC1抑制剂，其中三种具有迄今为止尚未与ABCC1抑制作用相关的支架。命中率最高的分子-噻吩并嘧啶-是ABCC1介导的钙黄绿素AM转运的中等效力，竞争性抑制剂，它也使过表达ABCC1的细胞对柔红霉素敏感。进一步的评估表明，它是ABCB1介导的钙黄绿素AM转运的中度有效竞争性抑制剂，是ABCG2介导的脱镁叶绿素A转运的非竞争性抑制剂。此外，硫代嘧啶还可以使ABCB1和ABCG2过表达的细胞分别对柔红霉素和SN-38敏感，其浓度范围使其成为文献中十种最佳的三重ABCC1 / ABCB1 / ABCG2抑制剂之一。此外，通过这种虚拟筛选方法还鉴定出了另外三种新的多靶点抑制剂。
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