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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.


Boxplot of molecular weights of inhibitors matched different pharmacophore hypotheses.
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f3: Boxplot of molecular weights of inhibitors matched different pharmacophore hypotheses.

Mentions: To investigate the specific patterns underlying each pharmacophore hypothesis, molecular weight (MW) of different types of inhibitors were compared. Overall, MATE1 inhibitors were slightly larger than OCT2 inhibitors, and more MATE1 inhibitors appeared in the range from 500–750 Da (Supplementary Figure S1). Among those four pharmacophore hypotheses, the average MW of HHR1 matched inhibitors was the smallest (Fig. 3), with the median of 360.36 Da and the maximum of 575.68 Da (Table 2). Most inhibitors matching HHR2 or AAAP are large in size with the median over 550 Da (Table 2). Some inhibitors with over 1000 Da can even be allowed by HHR2 and AAAP. Inhibitors matching DRR cover a wide range of molecular weights, in which the majority of inhibitors are relative small with the median of 438.69 Da, but large inhibitors with 720 Da are also allowed. Generally, the inhibitors matching HHR1 are relatively small, but the inhibitors matching HHR2 or AAAP are much larger.


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)

Boxplot of molecular weights of inhibitors matched different pharmacophore hypotheses.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Boxplot of molecular weights of inhibitors matched different pharmacophore hypotheses.
Mentions: To investigate the specific patterns underlying each pharmacophore hypothesis, molecular weight (MW) of different types of inhibitors were compared. Overall, MATE1 inhibitors were slightly larger than OCT2 inhibitors, and more MATE1 inhibitors appeared in the range from 500–750 Da (Supplementary Figure S1). Among those four pharmacophore hypotheses, the average MW of HHR1 matched inhibitors was the smallest (Fig. 3), with the median of 360.36 Da and the maximum of 575.68 Da (Table 2). Most inhibitors matching HHR2 or AAAP are large in size with the median over 550 Da (Table 2). Some inhibitors with over 1000 Da can even be allowed by HHR2 and AAAP. Inhibitors matching DRR cover a wide range of molecular weights, in which the majority of inhibitors are relative small with the median of 438.69 Da, but large inhibitors with 720 Da are also allowed. Generally, the inhibitors matching HHR1 are relatively small, but the inhibitors matching HHR2 or AAAP are much larger.

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.