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Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as TNF-α Release Inhibitors by in Silico Explorations.

Wang Y, Wu M, Ai C, Wang Y - Int J Mol Sci (2015)

Bottom Line: Both the resultant CoMFA and CoMSIA models exhibited satisfactory predictability (with Q(2) (cross-validated correlation coefficient) = 0.557, R(2)ncv (non-cross-validated correlation coefficient) = 0.740, R(2)pre (predicted correlation coefficient) = 0.749 and Q(2) = 0.598, R(2)ncv = 0.767, R(2)pre = 0.860, respectively).Good consistency was observed between the 3D-QSAR models and the pharmacophore model that the hydrophobic interaction and hydrogen bonds play crucial roles in the mechanism of actions.All these models have extended the understanding of imidazole-based compounds in the structure-activity relationship, and are useful for rational design and screening of novel 2-thioimidazole-based TNF-α release inhibitors.

View Article: PubMed Central - PubMed

Affiliation: Lab of Systems Pharmacology, College of Life Sciences, Northwest A&F (Agriculture and Forestry) University, Yangling 712100, China. yuan-w-09@nwsuaf.edu.cn.

ABSTRACT
Presently, 151 widely-diverse pyridinylimidazole-based compounds that show inhibitory activities at the TNF-α release were investigated. By using the distance comparison technique (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular similarity index analysis (CoMSIA) methods, the pharmacophore models and the three-dimensional quantitative structure-activity relationships (3D-QSAR) of the compounds were explored. The proposed pharmacophore model, including two hydrophobic sites, two aromatic centers, two H-bond donor atoms, two H-bond acceptor atoms, and two H-bond donor sites characterizes the necessary structural features of TNF-α release inhibitors. Both the resultant CoMFA and CoMSIA models exhibited satisfactory predictability (with Q(2) (cross-validated correlation coefficient) = 0.557, R(2)ncv (non-cross-validated correlation coefficient) = 0.740, R(2)pre (predicted correlation coefficient) = 0.749 and Q(2) = 0.598, R(2)ncv = 0.767, R(2)pre = 0.860, respectively). Good consistency was observed between the 3D-QSAR models and the pharmacophore model that the hydrophobic interaction and hydrogen bonds play crucial roles in the mechanism of actions. The corresponding contour maps generated by these models provide more diverse information about the key intermolecular interactions of inhibitors with the surrounding environment. All these models have extended the understanding of imidazole-based compounds in the structure-activity relationship, and are useful for rational design and screening of novel 2-thioimidazole-based TNF-α release inhibitors.

No MeSH data available.


The interaction features of compound 3v impacting the antagonistic activity obtained from our present work.
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ijms-16-20118-f008: The interaction features of compound 3v impacting the antagonistic activity obtained from our present work.

Mentions: In the present work, a series of CoMFA, CoMSIA, and pharmacophore studies were performed on 151 imidazole-based TNF-α release inhibitors (see Figure 8). Both the reliability and predictivity of the resultant optimal CoMFA and CoMSIA models (with Q2 = 0.557, R2ncv = 0.740, R2pre = 0.748 and Q2 = 0.598, R2ncv = 0.767, R2pre = 0.860, respectively) were validated by their high Q2, R2ncv, and R2pre values. The corresponding contour maps generated by these models provide more diverse information about the key intermolecular interactions of inhibitors with the surrounding environment. A good consistency was also observed between the QSAR models and pharmacophore modeling studies. To sum up, our findings are:


Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as TNF-α Release Inhibitors by in Silico Explorations.

Wang Y, Wu M, Ai C, Wang Y - Int J Mol Sci (2015)

The interaction features of compound 3v impacting the antagonistic activity obtained from our present work.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4613192&req=5

ijms-16-20118-f008: The interaction features of compound 3v impacting the antagonistic activity obtained from our present work.
Mentions: In the present work, a series of CoMFA, CoMSIA, and pharmacophore studies were performed on 151 imidazole-based TNF-α release inhibitors (see Figure 8). Both the reliability and predictivity of the resultant optimal CoMFA and CoMSIA models (with Q2 = 0.557, R2ncv = 0.740, R2pre = 0.748 and Q2 = 0.598, R2ncv = 0.767, R2pre = 0.860, respectively) were validated by their high Q2, R2ncv, and R2pre values. The corresponding contour maps generated by these models provide more diverse information about the key intermolecular interactions of inhibitors with the surrounding environment. A good consistency was also observed between the QSAR models and pharmacophore modeling studies. To sum up, our findings are:

Bottom Line: Both the resultant CoMFA and CoMSIA models exhibited satisfactory predictability (with Q(2) (cross-validated correlation coefficient) = 0.557, R(2)ncv (non-cross-validated correlation coefficient) = 0.740, R(2)pre (predicted correlation coefficient) = 0.749 and Q(2) = 0.598, R(2)ncv = 0.767, R(2)pre = 0.860, respectively).Good consistency was observed between the 3D-QSAR models and the pharmacophore model that the hydrophobic interaction and hydrogen bonds play crucial roles in the mechanism of actions.All these models have extended the understanding of imidazole-based compounds in the structure-activity relationship, and are useful for rational design and screening of novel 2-thioimidazole-based TNF-α release inhibitors.

View Article: PubMed Central - PubMed

Affiliation: Lab of Systems Pharmacology, College of Life Sciences, Northwest A&F (Agriculture and Forestry) University, Yangling 712100, China. yuan-w-09@nwsuaf.edu.cn.

ABSTRACT
Presently, 151 widely-diverse pyridinylimidazole-based compounds that show inhibitory activities at the TNF-α release were investigated. By using the distance comparison technique (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular similarity index analysis (CoMSIA) methods, the pharmacophore models and the three-dimensional quantitative structure-activity relationships (3D-QSAR) of the compounds were explored. The proposed pharmacophore model, including two hydrophobic sites, two aromatic centers, two H-bond donor atoms, two H-bond acceptor atoms, and two H-bond donor sites characterizes the necessary structural features of TNF-α release inhibitors. Both the resultant CoMFA and CoMSIA models exhibited satisfactory predictability (with Q(2) (cross-validated correlation coefficient) = 0.557, R(2)ncv (non-cross-validated correlation coefficient) = 0.740, R(2)pre (predicted correlation coefficient) = 0.749 and Q(2) = 0.598, R(2)ncv = 0.767, R(2)pre = 0.860, respectively). Good consistency was observed between the 3D-QSAR models and the pharmacophore model that the hydrophobic interaction and hydrogen bonds play crucial roles in the mechanism of actions. The corresponding contour maps generated by these models provide more diverse information about the key intermolecular interactions of inhibitors with the surrounding environment. All these models have extended the understanding of imidazole-based compounds in the structure-activity relationship, and are useful for rational design and screening of novel 2-thioimidazole-based TNF-α release inhibitors.

No MeSH data available.