ABCC1公司
化学
钙黄绿素
Abcg2型
虚拟筛选
柔红霉素
非竞争性抑制
运输机
药理学
ATP结合盒运输机
生物化学
计算生物学
药效团
生物
医学
酶
内科学
基因
白血病
膜
作者
Katja Silbermann,Sven Marcel Stefan,Randa Elshawadfy,Vigneshwaran Namasivayam,Michael Wiese
标识
DOI:10.1021/acs.jmedchem.8b01821
摘要
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.
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