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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

Docked conformations derived for molecule 11 of EPK (shown in ball and stick model) with the β5 subunit of human proteasome. H-bonds formed between residues and molecule directly and mediated by water indirectly are shown as dotted lines with blue and red color, respectively. W3027 and W3046 represent water molecules. The nonpolar hydrogen atoms are removed for clarity.
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f8-ijms-12-01807: Docked conformations derived for molecule 11 of EPK (shown in ball and stick model) with the β5 subunit of human proteasome. H-bonds formed between residues and molecule directly and mediated by water indirectly are shown as dotted lines with blue and red color, respectively. W3027 and W3046 represent water molecules. The nonpolar hydrogen atoms are removed for clarity.

Mentions: The binding mode of compound 11, shown in Figure 8, is taken as an example for analysis. The ligand core is anchored in the binding site via four H-bonds and two water-mediated contacts with the protein. The oxygen at C5-position of the main chain forms a H-bond with the backbone NH of Thr80 (–O···HN, 2.01 Å, 152.4°), and the oxygen at C2-position of the main chain forms a H-bond with the side chain of Thr60 (-O···HO, 1.78 Å, 131.9°). While the two hydrogen atoms at the N4- and N7- positions of the main chain form two H-bonds with the backbone carboxyl group of Gly106 (-O···HN, 1.69 Å, 146.5°) and the backbone carbonyl group of Thr80 (–O···HN, 1.85 Å, 160.0°), respectively. Additionally, it is worth noting that water plays an essential role in mediating the interaction between EPK and the β5 subunit. The interaction between the ketone oxygen with the side chain of Ser189 and the carboxyl group of Tyr228 is bridged by a structural water molecule (W3046), and the interaction between the oxygen at the C8-position of the main chain and the nitrogen of the isoxazole ring with Ala108 and Ala109 is bridged by another structural water molecule (W3027).


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)

Docked conformations derived for molecule 11 of EPK (shown in ball and stick model) with the β5 subunit of human proteasome. H-bonds formed between residues and molecule directly and mediated by water indirectly are shown as dotted lines with blue and red color, respectively. W3027 and W3046 represent water molecules. The nonpolar hydrogen atoms are removed for clarity.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f8-ijms-12-01807: Docked conformations derived for molecule 11 of EPK (shown in ball and stick model) with the β5 subunit of human proteasome. H-bonds formed between residues and molecule directly and mediated by water indirectly are shown as dotted lines with blue and red color, respectively. W3027 and W3046 represent water molecules. The nonpolar hydrogen atoms are removed for clarity.
Mentions: The binding mode of compound 11, shown in Figure 8, is taken as an example for analysis. The ligand core is anchored in the binding site via four H-bonds and two water-mediated contacts with the protein. The oxygen at C5-position of the main chain forms a H-bond with the backbone NH of Thr80 (–O···HN, 2.01 Å, 152.4°), and the oxygen at C2-position of the main chain forms a H-bond with the side chain of Thr60 (-O···HO, 1.78 Å, 131.9°). While the two hydrogen atoms at the N4- and N7- positions of the main chain form two H-bonds with the backbone carboxyl group of Gly106 (-O···HN, 1.69 Å, 146.5°) and the backbone carbonyl group of Thr80 (–O···HN, 1.85 Å, 160.0°), respectively. Additionally, it is worth noting that water plays an essential role in mediating the interaction between EPK and the β5 subunit. The interaction between the ketone oxygen with the side chain of Ser189 and the carboxyl group of Tyr228 is bridged by a structural water molecule (W3046), and the interaction between the oxygen at the C8-position of the main chain and the nitrogen of the isoxazole ring with Ala108 and Ala109 is bridged by another structural water molecule (W3027).

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