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

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 inhi...

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Bibliographic Details
Published in:Scientific reports 2015-09, Vol.5 (1), p.13684-13684, Article 13684
Main Authors: Xu, Yuan, Liu, Xian, Wang, Yulan, Zhou, Nannan, Peng, Jianlong, Gong, Likun, Ren, Jing, Luo, Cheng, Luo, Xiaomin, Jiang, Hualiang, Chen, Kaixian, Zheng, Mingyue
Format: Article
Language:English
Subjects:
631/114/2397
631/154
Combinatorial Chemistry Techniques
Conformation
Humanities and Social Sciences
Hydrophobicity
Hypotheses
Inhibitors
Ligands
Models, Biological
Models, Molecular
Molecular Docking Simulation
Molecular Weight
multidisciplinary
Oct-2 protein
Organic Cation Transport Proteins - antagonists & inhibitors
Organic Cation Transport Proteins - metabolism
Organic cation transporter
Science
Toxins
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Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep13684