Combinatorial Pharmacophore Modeling of Multidrug and Toxin Extrusion Transporter 1 Inhibitors: a Theoretical Perspective for Understanding Multiple Inhibitory Mechanisms

doi:10.1038/srep13684

	Combinatorial Pharmacophore Modeling of Multidrug and Toxin Extrusion Transporter 1 Inhibitors: a Theoretical Perspective for Understanding Multiple Inhibitory Mechanisms
	Xu, Yuan 1; Liu, Xian 1; Wang, Yulan 1; Zhou, Nannan 1; Peng, Jianlong 1; Gong, Likun 2; Ren, Jing 2; Luo, Cheng 1; Luo, Xiaomin 1; Jiang, Hualiang1,3 ; Chen, Kaixian1,3 ; Zheng, Mingyue 1
	2015-09-02
发表期刊	SCIENTIFIC REPORTS
ISSN	2045-2322
卷号	5
发表状态	已发表
DOI	10.1038/srep13684
摘要	A combinatorial pharmacophore (CP) model for Multidrug and toxin extrusion 1 (MATE1/SLC47A1) inhibitors was developed based on a data set including 881 compounds. The CP model comprises four individual pharmacophore hypotheses, HHR1, DRR, HHR2 and AAAP, which can successfully identify the MATE1 inhibitors with an overall accuracy around 75%. The model emphasizes the importance of aromatic ring and hydrophobicity as two important structural determinants for MATE1 inhibition. Compared with the pharmacophore model of Organic Cation Transporter 2 (OCT2/SLC22A2), a functional related transporter of MATE1, the hypotheses of AAAP and PRR5 are suggested to be responsible for their ligand selectivity, while HHR a common recognition pattern for their dual inhibition. A series of analysis including molecular sizes of inhibitors matching different hypotheses, matching of representative MATE1 inhibitors and molecular docking indicated that the small inhibitors matching HHR1 and DRR involve in competitive inhibition, while the relatively large inhibitors matching AAAP are responsible for the noncompetitive inhibition by locking the conformation changing of MATE1. In light of the results, a hypothetical model for inhibiting transporting mediated by MATE1 was proposed.
收录类别	SCI
语种	英语
资助项目	National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program"[2014ZX09507002-005-012] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program"[2012ZX09301001-006]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000360540600001
出版者	NATURE PUBLISHING GROUP
WOS关键词	ORGANIC CATION TRANSPORTER-2 ; MATE1 ; DATABASE ; PROTEIN ; KIDNEY
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/2140
专题	免疫化学研究所_特聘教授组_蒋华良组生命科学与技术学院_特聘教授组_陈凯先组
通讯作者	Gong, Likun
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Ctr Drug Safety Evaluat & Res, Shanghai Inst Mat Med, Shanghai 200031, Peoples R China 3.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China
推荐引用方式 GB/T 7714	Xu, Yuan,Liu, Xian,Wang, Yulan,et al. Combinatorial Pharmacophore Modeling of Multidrug and Toxin Extrusion Transporter 1 Inhibitors: a Theoretical Perspective for Understanding Multiple Inhibitory Mechanisms[J]. SCIENTIFIC REPORTS,2015,5.
APA	Xu, Yuan.,Liu, Xian.,Wang, Yulan.,Zhou, Nannan.,Peng, Jianlong.,...&Zheng, Mingyue.(2015).Combinatorial Pharmacophore Modeling of Multidrug and Toxin Extrusion Transporter 1 Inhibitors: a Theoretical Perspective for Understanding Multiple Inhibitory Mechanisms.SCIENTIFIC REPORTS,5.
MLA	Xu, Yuan,et al."Combinatorial Pharmacophore Modeling of Multidrug and Toxin Extrusion Transporter 1 Inhibitors: a Theoretical Perspective for Understanding Multiple Inhibitory Mechanisms".SCIENTIFIC REPORTS 5(2015).