Combinatorial Pharmacophore Modeling of Organic Cation Transporter 2 (OCT2) Inhibitors: Insights into Multiple Inhibitory Mechanisms
文献类型：期刊论文
| 作者 | Xu, Yuan2; Liu, Xian2; Li, Shanshan2; Zhou, Nannan1,3; Gong, Likun2 ; Luo, Cheng2; Luo, Xiaomin2; Zheng, Mingyue2; Jiang, Hualiang1,2,3; Chen, Kaixian2
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| 刊名 | MOLECULAR PHARMACEUTICS
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| 出版日期 | 2013-12 |
| 卷号 | 10期号:12页码:4611-4619 |
| 关键词 | organic cation transporter 2 (OCT2) drug clearance drug-drug interaction (DDI) pharmacophore multiple inhibition mechanism |
| ISSN号 | 1543-8384 |
| DOI | 10.1021/mp400423g |
| 文献子类 | Article |
| 英文摘要 | Organic cation transporter 2 (OCT2) is responsible for the entry step of many drugs in renal elimination, of which the changing activity may cause unwanted drug drug interactions (DDIs). To develop drugs with favorable safety profile and provide instruction for rational clinical drug administration, it is of great interest to investigate the multiple mechanisms of OCT2 inhibition. In this study, we designed a combinatorial scheme to screen the optimum combination of pharmacophores from a pool of hypotheses established based on 162 OCT2 inhibitors. Among them, one single pharmacophore hypothesis represents a potential binding mode that may account for one unique inhibitory mechanism, and the obtained pharmacophore combination describes the multimechanisms of OCT2 inhibition. The final model consists of four individual pharmacophores, i.e., DHPR18, APR2, PRR5 and HHR4. Given a query ligand, it is considered as an inhibitor if it matches at least one of the hypotheses, or a noninhibitor if it fails to match any of four hypotheses. Our combinatorial pharmacophore model performs reasonably well to discriminate inhibitors and noninhibitors, yielding an overall accuracy around 0.70 for a test set containing 81 OCT2 inhibitors and 218 noninhibitors. Intriguingly, we found that the number of matched hypotheses was positively correlated with inhibition rate, which coincides with the pharmacophore modeling result of P-gp substrate binding. Further analysis suggested that the hypothesis PRRS was responsible for competitive inhibition of OCT2, and other hypotheses were important for interaction between the inhibitor and OCT2. In light of the results, a hypothetical model for inhibiting transporting mediated by OCT2 was proposed. |
| WOS关键词 | MULTIDRUG-RESISTANCE ; SUBSTRATE-BINDING ; IN-VITRO ; MEMBRANE TRANSPORTERS ; P-GLYCOPROTEIN ; CDNA CLONING ; HOCT2 ; DETERMINANTS ; DRUGS ; ORGANIC-CATION-TRANSPORTER-2 |
| 资助项目 | National High Technology Research and Development Program of China[2012AA020302] ; State Key Program of Basic Research of China[2009CB918502] ; National Natural Science Foundation of China[21021063] ; National Natural Science Foundation of China[81230076] ; National Natural Science Foundation of China[81001399] ; National Natural Science Foundation of China[21210003] ; Key projects of National Science and Technology Pillar Program[2013ZX09507-004 2012ZX09301001-006] |
| WOS研究方向 | Research & Experimental Medicine ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000327831500021 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277360]  |
| 专题 | 药物发现与设计中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Luo, Xiaomin |
| 作者单位 | 1.E China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 3.E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab Chem Biol, Shanghai 200237, Peoples R China |
| 推荐引用方式 GB/T 7714 | Xu, Yuan,Liu, Xian,Li, Shanshan,et al. Combinatorial Pharmacophore Modeling of Organic Cation Transporter 2 (OCT2) Inhibitors: Insights into Multiple Inhibitory Mechanisms[J]. MOLECULAR PHARMACEUTICS,2013,10(12):4611-4619. |
| APA | Xu, Yuan.,Liu, Xian.,Li, Shanshan.,Zhou, Nannan.,Gong, Likun.,...&Chen, Kaixian.(2013).Combinatorial Pharmacophore Modeling of Organic Cation Transporter 2 (OCT2) Inhibitors: Insights into Multiple Inhibitory Mechanisms.MOLECULAR PHARMACEUTICS,10(12),4611-4619. |
| MLA | Xu, Yuan,et al."Combinatorial Pharmacophore Modeling of Organic Cation Transporter 2 (OCT2) Inhibitors: Insights into Multiple Inhibitory Mechanisms".MOLECULAR PHARMACEUTICS 10.12(2013):4611-4619. |
入库方式： OAI收割
来源：上海药物研究所
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