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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.


The structure of transporting chamber.C lobe, central lobe and N lobe are colored in grey, orange, and magenta, respectively. The residues that occupied the binding space of C lobe are displayed in sticks.
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f5: The structure of transporting chamber.C lobe, central lobe and N lobe are colored in grey, orange, and magenta, respectively. The residues that occupied the binding space of C lobe are displayed in sticks.

Mentions: The above analyses revealed that different pharmacophores are related to different binding patterns of MATE1 inhibitors. It is therefore interesting to investigate the putative binding modes of these inhibitors within the structure of hMATE1. Sequence alignment of hMATE1 and two template structures NorM-VC and pfMATE was provided in Supplementary Figure S2. Three homology models of hMATE1 constructed basing on the template of pfMATE, NorM-VC and both these two structures were compared. Among them, the model based on the pfMATE got the highest QMEAN6 score of 0.484 (Table 3). The PROCHEK result of the model based on the pfMATE show that the model is also the one showing the most reasonable stereo chemical features, where 99.5% of residues have been found in the favored regions (Supplementary Figure S3b), suggesting the high quality of the resulted model. This model was therefore selected for the followed analyses. As shown in Supplementary Figure S3a, all twelve transmembrane domains (TMD) were successfully constructed and the model can be well aligned to the structure of pfMATE. In the homology model structure, two bundles of six transmembrane helices, N-terminal half (TMD1–6) and C-terminal half (TMD7–12), formed a large and outward-opening transporting chamber. Particularly, the transporting chamber can be divided into an N lobe, a central lobe and a C lobe cavity (Fig. 5), among which the N lobe is smaller than the central lobe and located deeper in the chamber. The central lobe cavity includes the rest of transporting chamber from the entrance to the bottom of the transporting pathway. In addition, C lobe cavity is much smaller than N lobe, and the binding space in C lobe is occupied by the non-conservative residuals Met272, Gln295 and Tyr299 on TMD7 and TMD8. This result is consistence with the crystal structure of pfMATE, where the residues located at the boundary of C lobe and central lobe and would interfere the entrance of C lobe12. Therefore, there are mainly two substrate binding sites in hMATE1, as revealed from our homology modeling structure.


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)

The structure of transporting chamber.C lobe, central lobe and N lobe are colored in grey, orange, and magenta, respectively. The residues that occupied the binding space of C lobe are displayed in sticks.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: The structure of transporting chamber.C lobe, central lobe and N lobe are colored in grey, orange, and magenta, respectively. The residues that occupied the binding space of C lobe are displayed in sticks.
Mentions: The above analyses revealed that different pharmacophores are related to different binding patterns of MATE1 inhibitors. It is therefore interesting to investigate the putative binding modes of these inhibitors within the structure of hMATE1. Sequence alignment of hMATE1 and two template structures NorM-VC and pfMATE was provided in Supplementary Figure S2. Three homology models of hMATE1 constructed basing on the template of pfMATE, NorM-VC and both these two structures were compared. Among them, the model based on the pfMATE got the highest QMEAN6 score of 0.484 (Table 3). The PROCHEK result of the model based on the pfMATE show that the model is also the one showing the most reasonable stereo chemical features, where 99.5% of residues have been found in the favored regions (Supplementary Figure S3b), suggesting the high quality of the resulted model. This model was therefore selected for the followed analyses. As shown in Supplementary Figure S3a, all twelve transmembrane domains (TMD) were successfully constructed and the model can be well aligned to the structure of pfMATE. In the homology model structure, two bundles of six transmembrane helices, N-terminal half (TMD1–6) and C-terminal half (TMD7–12), formed a large and outward-opening transporting chamber. Particularly, the transporting chamber can be divided into an N lobe, a central lobe and a C lobe cavity (Fig. 5), among which the N lobe is smaller than the central lobe and located deeper in the chamber. The central lobe cavity includes the rest of transporting chamber from the entrance to the bottom of the transporting pathway. In addition, C lobe cavity is much smaller than N lobe, and the binding space in C lobe is occupied by the non-conservative residuals Met272, Gln295 and Tyr299 on TMD7 and TMD8. This result is consistence with the crystal structure of pfMATE, where the residues located at the boundary of C lobe and central lobe and would interfere the entrance of C lobe12. Therefore, there are mainly two substrate binding sites in hMATE1, as revealed from our homology modeling structure.

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.