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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.


Related in: MedlinePlus

Hypothetic models for MATE1 inhibition.Sub: substrate. Inhibitors matching HHR1 or DRR compete for substrate binding site and competitively inhibit the transporting of the substrate. Inhibitors matching AAAP lock the transporter conformation transformation and noncompetitively inhibit the transporting of the substrate. The binding site of inhibitors matching HHR2 can be in either the N lobe or the central lobe.
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f8: Hypothetic models for MATE1 inhibition.Sub: substrate. Inhibitors matching HHR1 or DRR compete for substrate binding site and competitively inhibit the transporting of the substrate. Inhibitors matching AAAP lock the transporter conformation transformation and noncompetitively inhibit the transporting of the substrate. The binding site of inhibitors matching HHR2 can be in either the N lobe or the central lobe.

Mentions: The analysis of molecular weight and representative inhibitors implied that HHR1 and DRR may involve in competitive inhibition, while AAAP may be responsible for noncompetitive inhibition. Docking result further supported our inference. Therefore, hypothetic models for hMATE1 inhibition are concluded that small inhibitors matching HHR1 and DRR can get into the transporting chamber, interact with MATE1 at relatively small substrate binding site located in inner chamber, and affect transportation by competing the binding site with the substrate. On the other hand, inhibitors matching AAAP which are usually large compounds could not be tolerated by the small substrate binding site but located in large central cavity, which may noncompetitively inhibited the MATE1 by locking the conformation changing (Fig. 8). Due to the small number of inhibitors which only match HHR2, it was still uncertain which kind of inhibition HHR2 involved in or by both in competitive and noncompetitive manner that HHR2 can affect MATE1 as the sites distribution almost same in N lobe and central lobe. Other noncompetitive inhibition that affected H+ binding or allosteric regulation may participate in the transporting process. Lacking of the specific experimental data, our model at present couldn’t cover these noncompetitive pattern.


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)

Hypothetic models for MATE1 inhibition.Sub: substrate. Inhibitors matching HHR1 or DRR compete for substrate binding site and competitively inhibit the transporting of the substrate. Inhibitors matching AAAP lock the transporter conformation transformation and noncompetitively inhibit the transporting of the substrate. The binding site of inhibitors matching HHR2 can be in either the N lobe or the central lobe.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f8: Hypothetic models for MATE1 inhibition.Sub: substrate. Inhibitors matching HHR1 or DRR compete for substrate binding site and competitively inhibit the transporting of the substrate. Inhibitors matching AAAP lock the transporter conformation transformation and noncompetitively inhibit the transporting of the substrate. The binding site of inhibitors matching HHR2 can be in either the N lobe or the central lobe.
Mentions: The analysis of molecular weight and representative inhibitors implied that HHR1 and DRR may involve in competitive inhibition, while AAAP may be responsible for noncompetitive inhibition. Docking result further supported our inference. Therefore, hypothetic models for hMATE1 inhibition are concluded that small inhibitors matching HHR1 and DRR can get into the transporting chamber, interact with MATE1 at relatively small substrate binding site located in inner chamber, and affect transportation by competing the binding site with the substrate. On the other hand, inhibitors matching AAAP which are usually large compounds could not be tolerated by the small substrate binding site but located in large central cavity, which may noncompetitively inhibited the MATE1 by locking the conformation changing (Fig. 8). Due to the small number of inhibitors which only match HHR2, it was still uncertain which kind of inhibition HHR2 involved in or by both in competitive and noncompetitive manner that HHR2 can affect MATE1 as the sites distribution almost same in N lobe and central lobe. Other noncompetitive inhibition that affected H+ binding or allosteric regulation may participate in the transporting process. Lacking of the specific experimental data, our model at present couldn’t cover these noncompetitive pattern.

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.


Related in: MedlinePlus