Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1
Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1
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DOI：
10.1021/jm8003152
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发表时间：
2008-10-09
影响因子：
7.3
通讯作者：
Artursson, Per
中科院分区：
文献类型：
--
作者：
Ahlin, Gustav;Karlsson, Johan;Artursson, Per
肝脏特异性有机阳离子转运蛋白（OCT1; SLC22A1）转运多种阳离子药物，包括降糖药二甲双胍和抗癌药物奥沙利铂和伊马替尼。在本研究中，我们探索注册口服药物的化学空间，目的是研究OCT1的抑制模式，并建立OCT1抑制的预测计算模型。在HEK293-OCT1细胞中共检测了191种结构不同的化合物。该试验确定了47种新的抑制剂，并确认了15种以前已知的抑制剂。在包括抗抑郁药在内的几种药物中都发现了OCT1抑制剂的富集。高亲脂性和正电荷是OCT1抑制的关键理化性质，而高分子偶极矩和许多氢键与OCT1抑制呈负相关。这些数据用于生成OCT1抑制剂的OPLS-DA模型；最终的模型正确预测了测试集中82%的抑制剂和88%的非抑制剂。
The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.