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

Xu Y, Liu X, Wang Y, Zhou N, Peng J, Gong L, Ren J, Luo C, Luo X, Jiang H, Chen K, Zheng M - Sci Rep (2015)

Bottom Line: 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%.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.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.

ABSTRACT
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.

No MeSH data available.


Histogram to compare the distribution of MATE1 selective, OCT2 selective and dual inhibitors in matching hypotheses.MATE1 selective inhibitors and OCT2 selective inhibitors are colored by blue and red, respectively. Bars show the percentage of particular inhibitors matching each pharmacophore hypothesis.
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f4: Histogram to compare the distribution of MATE1 selective, OCT2 selective and dual inhibitors in matching hypotheses.MATE1 selective inhibitors and OCT2 selective inhibitors are colored by blue and red, respectively. Bars show the percentage of particular inhibitors matching each pharmacophore hypothesis.

Mentions: In our data set, there are 45 MATE1 selective inhibitors, 203 OCT2 selective inhibitors and 39 dual inhibitors. In order to understand which pharmacophore features differentiate three types of inhibitors, the matching pharmacophore hypotheses of three types of inhibitors were further exploited. Pharmacophore hypotheses from MATE1 CP model and OCT2 CP model were searched by OCT2 selective and MATE1 selective inhibitors, respectively. Figure 4 shows the differences of these different inhibitors on matching altogether eight pharmacophore hypotheses from both MATE1 and OCT2 CP models. It can be found that AAAP can better discriminate between OCT2 and MATE1 selective inhibitors, where a very small number of OCT2 selective inhibitors and a large number of MATE1 selective inhibitors can match the pharmacophore. Wittwer et al. reported that the range of molecular weight and volume of MATE1 inhibitors were much wider than OCT2 inhibitors9, which means that MATE1 can tolerate much larger ligands than OCT2. Therefore, the MATE1selective inhibition represented by AAAP suggest that MATE1 should have a more spacious transporting cavity as compared to OCT2. For OCT2 selective inhibition, nearly equal amount of OCT2 selective inhibitors match APR2 and PRR5, respectively, but much fewer MATE1 selective inhibitors can match PRR5. Our previous study has revealed that PRR5 is involved in the competitive inhibition of ASP+ in OCT210. The current study suggests that PRR5 is also important for its OCT2 selectivity over MATE1. Remarkably, both models emphasized the role of two hydrophobic and one ring. Among three HHR hypotheses, HHR1 derived for MATE1 and HHR4 derived for OCT2 show similar structural arrangement (Supplementary Table 2 and Supplementary Table 4), and these two pharmacophores can be matched by more than half of dual MATE1 and OCT2 inhibitors. These results suggested that HHR1 and HHR4 are the common interaction pattern shared by both MATE1 and OCT2. Once the molecule matched HHR1 or HHR4, it is likely to be a dual inhibitor of MATE1 and OCT2.


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

Xu Y, Liu X, Wang Y, Zhou N, Peng J, Gong L, Ren J, Luo C, Luo X, Jiang H, Chen K, Zheng M - Sci Rep (2015)

Histogram to compare the distribution of MATE1 selective, OCT2 selective and dual inhibitors in matching hypotheses.MATE1 selective inhibitors and OCT2 selective inhibitors are colored by blue and red, respectively. Bars show the percentage of particular inhibitors matching each pharmacophore hypothesis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556958&req=5

f4: Histogram to compare the distribution of MATE1 selective, OCT2 selective and dual inhibitors in matching hypotheses.MATE1 selective inhibitors and OCT2 selective inhibitors are colored by blue and red, respectively. Bars show the percentage of particular inhibitors matching each pharmacophore hypothesis.
Mentions: In our data set, there are 45 MATE1 selective inhibitors, 203 OCT2 selective inhibitors and 39 dual inhibitors. In order to understand which pharmacophore features differentiate three types of inhibitors, the matching pharmacophore hypotheses of three types of inhibitors were further exploited. Pharmacophore hypotheses from MATE1 CP model and OCT2 CP model were searched by OCT2 selective and MATE1 selective inhibitors, respectively. Figure 4 shows the differences of these different inhibitors on matching altogether eight pharmacophore hypotheses from both MATE1 and OCT2 CP models. It can be found that AAAP can better discriminate between OCT2 and MATE1 selective inhibitors, where a very small number of OCT2 selective inhibitors and a large number of MATE1 selective inhibitors can match the pharmacophore. Wittwer et al. reported that the range of molecular weight and volume of MATE1 inhibitors were much wider than OCT2 inhibitors9, which means that MATE1 can tolerate much larger ligands than OCT2. Therefore, the MATE1selective inhibition represented by AAAP suggest that MATE1 should have a more spacious transporting cavity as compared to OCT2. For OCT2 selective inhibition, nearly equal amount of OCT2 selective inhibitors match APR2 and PRR5, respectively, but much fewer MATE1 selective inhibitors can match PRR5. Our previous study has revealed that PRR5 is involved in the competitive inhibition of ASP+ in OCT210. The current study suggests that PRR5 is also important for its OCT2 selectivity over MATE1. Remarkably, both models emphasized the role of two hydrophobic and one ring. Among three HHR hypotheses, HHR1 derived for MATE1 and HHR4 derived for OCT2 show similar structural arrangement (Supplementary Table 2 and Supplementary Table 4), and these two pharmacophores can be matched by more than half of dual MATE1 and OCT2 inhibitors. These results suggested that HHR1 and HHR4 are the common interaction pattern shared by both MATE1 and OCT2. Once the molecule matched HHR1 or HHR4, it is likely to be a dual inhibitor of MATE1 and OCT2.

Bottom Line: 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%.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.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.

ABSTRACT
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.

No MeSH data available.