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Combined 3D-QSAR, molecular docking and molecular dynamics study on derivatives of peptide epoxyketone and tyropeptin-boronic acid as inhibitors against the β5 subunit of human 20S proteasome.

Liu J, Zhang H, Xiao Z, Wang F, Wang X, Wang Y - Int J Mol Sci (2011)

Bottom Line: The study resulted in two types of satisfactory 3D-QSAR models, i.e., the CoMFA model (Q(2) = 0.462, R(2) (pred) = 0.820) for epoxyketone inhibitors (EPK) and the CoMSIA model (Q(2) = 0.622, R(2) (pred) = 0.821) for tyropeptin-boronic acid derivatives (TBA).MD simulations further indicated that the binding modes of each conformation derived from docking is stable and in accord with the corresponding structure extracted from MD simulation overall.These results can offer useful theoretical references for designing more potent PIs.

View Article: PubMed Central - PubMed

Affiliation: College of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, China.

ABSTRACT
An abnormal ubiquitin-proteasome is found in many human diseases, especially in cancer, and has received extensive attention as a promising therapeutic target in recent years. In this work, several in silico models have been built with two classes of proteasome inhibitors (PIs) by using 3D-QSAR, homology modeling, molecular docking and molecular dynamics (MD) simulations. The study resulted in two types of satisfactory 3D-QSAR models, i.e., the CoMFA model (Q(2) = 0.462, R(2) (pred) = 0.820) for epoxyketone inhibitors (EPK) and the CoMSIA model (Q(2) = 0.622, R(2) (pred) = 0.821) for tyropeptin-boronic acid derivatives (TBA). From the contour maps, some key structural factors responsible for the activity of these two series of PIs are revealed. For EPK inhibitors, the N-cap part should have higher electropositivity; a large substituent such as a benzene ring is favored at the C6-position. In terms of TBA inhibitors, hydrophobic substituents with a larger size anisole group are preferential at the C8-position; higher electropositive substituents like a naphthalene group at the C3-position can enhance the activity of the drug by providing hydrogen bond interaction with the protein target. Molecular docking disclosed that residues Thr60, Thr80, Gly106 and Ser189 play a pivotal role in maintaining the drug-target interactions, which are consistent with the contour maps. MD simulations further indicated that the binding modes of each conformation derived from docking is stable and in accord with the corresponding structure extracted from MD simulation overall. These results can offer useful theoretical references for designing more potent PIs.

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Related in: MedlinePlus

CoMFA StDev*Coeff contour maps of EPK. (A) steric field contour map (green: favored, yellow: disfavored); (B) electrostatic field contour map (red: disfavored areas of positive potential; blue: favored areas of positive potential). Compound 11 is shown in tubes as a reference.
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f5-ijms-12-01807: CoMFA StDev*Coeff contour maps of EPK. (A) steric field contour map (green: favored, yellow: disfavored); (B) electrostatic field contour map (red: disfavored areas of positive potential; blue: favored areas of positive potential). Compound 11 is shown in tubes as a reference.

Mentions: The greatest advantage of the 3D-QSAR modeling is the visualization of the results as 3D coefficient contour plots, which are helpful for us to further understand the nature of the receptor-ligand binding regions and the effects of these regions on steric, electrostatic, hydrophobic, H-bond donor and receptor fields for the biological activity. With consideration of both the internal and external predictive powers, the ligand-based CoMFA model for EPK is selected for each conformation to construct the stdev*coeff contour maps to view effects on the target features, while the ligand-based CoMSIA model is used for TBA. The maps generated depict regions having scaled coefficients greater than 80% (favored) or less than 20% (disfavored). For visualization, molecule 11 of EPK and molecular 2 of TBA is selected to demonstrate the contour maps (Figure 5 and Figure 6, respectively).


Combined 3D-QSAR, molecular docking and molecular dynamics study on derivatives of peptide epoxyketone and tyropeptin-boronic acid as inhibitors against the β5 subunit of human 20S proteasome.

Liu J, Zhang H, Xiao Z, Wang F, Wang X, Wang Y - Int J Mol Sci (2011)

CoMFA StDev*Coeff contour maps of EPK. (A) steric field contour map (green: favored, yellow: disfavored); (B) electrostatic field contour map (red: disfavored areas of positive potential; blue: favored areas of positive potential). Compound 11 is shown in tubes as a reference.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3111635&req=5

f5-ijms-12-01807: CoMFA StDev*Coeff contour maps of EPK. (A) steric field contour map (green: favored, yellow: disfavored); (B) electrostatic field contour map (red: disfavored areas of positive potential; blue: favored areas of positive potential). Compound 11 is shown in tubes as a reference.
Mentions: The greatest advantage of the 3D-QSAR modeling is the visualization of the results as 3D coefficient contour plots, which are helpful for us to further understand the nature of the receptor-ligand binding regions and the effects of these regions on steric, electrostatic, hydrophobic, H-bond donor and receptor fields for the biological activity. With consideration of both the internal and external predictive powers, the ligand-based CoMFA model for EPK is selected for each conformation to construct the stdev*coeff contour maps to view effects on the target features, while the ligand-based CoMSIA model is used for TBA. The maps generated depict regions having scaled coefficients greater than 80% (favored) or less than 20% (disfavored). For visualization, molecule 11 of EPK and molecular 2 of TBA is selected to demonstrate the contour maps (Figure 5 and Figure 6, respectively).

Bottom Line: The study resulted in two types of satisfactory 3D-QSAR models, i.e., the CoMFA model (Q(2) = 0.462, R(2) (pred) = 0.820) for epoxyketone inhibitors (EPK) and the CoMSIA model (Q(2) = 0.622, R(2) (pred) = 0.821) for tyropeptin-boronic acid derivatives (TBA).MD simulations further indicated that the binding modes of each conformation derived from docking is stable and in accord with the corresponding structure extracted from MD simulation overall.These results can offer useful theoretical references for designing more potent PIs.

View Article: PubMed Central - PubMed

Affiliation: College of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, China.

ABSTRACT
An abnormal ubiquitin-proteasome is found in many human diseases, especially in cancer, and has received extensive attention as a promising therapeutic target in recent years. In this work, several in silico models have been built with two classes of proteasome inhibitors (PIs) by using 3D-QSAR, homology modeling, molecular docking and molecular dynamics (MD) simulations. The study resulted in two types of satisfactory 3D-QSAR models, i.e., the CoMFA model (Q(2) = 0.462, R(2) (pred) = 0.820) for epoxyketone inhibitors (EPK) and the CoMSIA model (Q(2) = 0.622, R(2) (pred) = 0.821) for tyropeptin-boronic acid derivatives (TBA). From the contour maps, some key structural factors responsible for the activity of these two series of PIs are revealed. For EPK inhibitors, the N-cap part should have higher electropositivity; a large substituent such as a benzene ring is favored at the C6-position. In terms of TBA inhibitors, hydrophobic substituents with a larger size anisole group are preferential at the C8-position; higher electropositive substituents like a naphthalene group at the C3-position can enhance the activity of the drug by providing hydrogen bond interaction with the protein target. Molecular docking disclosed that residues Thr60, Thr80, Gly106 and Ser189 play a pivotal role in maintaining the drug-target interactions, which are consistent with the contour maps. MD simulations further indicated that the binding modes of each conformation derived from docking is stable and in accord with the corresponding structure extracted from MD simulation overall. These results can offer useful theoretical references for designing more potent PIs.

Show MeSH
Related in: MedlinePlus