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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

(A) H-bond distance during MD simulations (D1:ligand@B-OH···NH of Thr60; D2: ligand@N7-O···HN of Ser189; D3: ligand@C4-O···O of Gly106); (B) The conformation derived for compound 2 (shown in ball and stick with blue color) with the β5 subunit of human proteasome in MD simulations. H-bonds formed by residues and molecule are shown as dotted lines with blue color. The nonpolar hydrogen atoms are removed for clarity.
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f14-ijms-12-01807: (A) H-bond distance during MD simulations (D1:ligand@B-OH···NH of Thr60; D2: ligand@N7-O···HN of Ser189; D3: ligand@C4-O···O of Gly106); (B) The conformation derived for compound 2 (shown in ball and stick with blue color) with the β5 subunit of human proteasome in MD simulations. H-bonds formed by residues and molecule are shown as dotted lines with blue color. The nonpolar hydrogen atoms are removed for clarity.

Mentions: By VMD software, we find that the conformation of compound 2 changed slightly overall during the dynamic process. Thus, the RMSD values of the compound 2-β5 subunit system as a whole with respect to the original structure of the docking complex are analyzed (shown in Figure 13A). We can see that the RMSD values of this system range from 0.6 to 1.7 Å, and are relatively stable after 1500 ps with the RMSD of about 1.2 Å, suggesting that the molecular systems behaved well thereafter. The low RMSD fluctuations confirm the feasibility of the binding poses predicted by Surflex dock. A superposition of the average structure of the ensemble for the last 100 ps and the docked structure is shown in Figure 13B. It is noted that there is no significant difference between the average structure extracted from MD simulations and the docked model of the complex, except the anisole group rotated 64°, showing the rationality and stability of the docking model. In order to explore the similarities and differences between the results of docking and MD simulation, the interactions between compound 2 and the β5 subunit was analyzed. From Figure 14B, we can see that four H-bonds formed during MD simulations. Among these four H-bonds, three formed at the same sites as those in docking mode with different distances and angles. The two oxygen atoms at the C7- and C4-positions of the main chain formed two stable H-bonds with the backbone NH of Ser189 (-O···HN, 2.82 Å, 121.1°) and backbone NH of Gly106 (-O···HN, 2.19 Å, 158.2°), respectively; the hydroxyl oxygen at the B1-position of the main chain formed a weak H-bond with the back bone NH of Thr60 (-O···HN, 3.10 Å, 144.6°). A new H-bond is formed between the other hydroxyl oxygen at the B1-position of the main chain and Thr80 (-O···HN, 2.16 Å, 166.7°). Similarly, we also detected variations of the three H-bond distances during the simulation process (shown in Figure 14A).


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)

(A) H-bond distance during MD simulations (D1:ligand@B-OH···NH of Thr60; D2: ligand@N7-O···HN of Ser189; D3: ligand@C4-O···O of Gly106); (B) The conformation derived for compound 2 (shown in ball and stick with blue color) with the β5 subunit of human proteasome in MD simulations. H-bonds formed by residues and molecule are shown as dotted lines with blue color. 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

f14-ijms-12-01807: (A) H-bond distance during MD simulations (D1:ligand@B-OH···NH of Thr60; D2: ligand@N7-O···HN of Ser189; D3: ligand@C4-O···O of Gly106); (B) The conformation derived for compound 2 (shown in ball and stick with blue color) with the β5 subunit of human proteasome in MD simulations. H-bonds formed by residues and molecule are shown as dotted lines with blue color. The nonpolar hydrogen atoms are removed for clarity.
Mentions: By VMD software, we find that the conformation of compound 2 changed slightly overall during the dynamic process. Thus, the RMSD values of the compound 2-β5 subunit system as a whole with respect to the original structure of the docking complex are analyzed (shown in Figure 13A). We can see that the RMSD values of this system range from 0.6 to 1.7 Å, and are relatively stable after 1500 ps with the RMSD of about 1.2 Å, suggesting that the molecular systems behaved well thereafter. The low RMSD fluctuations confirm the feasibility of the binding poses predicted by Surflex dock. A superposition of the average structure of the ensemble for the last 100 ps and the docked structure is shown in Figure 13B. It is noted that there is no significant difference between the average structure extracted from MD simulations and the docked model of the complex, except the anisole group rotated 64°, showing the rationality and stability of the docking model. In order to explore the similarities and differences between the results of docking and MD simulation, the interactions between compound 2 and the β5 subunit was analyzed. From Figure 14B, we can see that four H-bonds formed during MD simulations. Among these four H-bonds, three formed at the same sites as those in docking mode with different distances and angles. The two oxygen atoms at the C7- and C4-positions of the main chain formed two stable H-bonds with the backbone NH of Ser189 (-O···HN, 2.82 Å, 121.1°) and backbone NH of Gly106 (-O···HN, 2.19 Å, 158.2°), respectively; the hydroxyl oxygen at the B1-position of the main chain formed a weak H-bond with the back bone NH of Thr60 (-O···HN, 3.10 Å, 144.6°). A new H-bond is formed between the other hydroxyl oxygen at the B1-position of the main chain and Thr80 (-O···HN, 2.16 Å, 166.7°). Similarly, we also detected variations of the three H-bond distances during the simulation process (shown in Figure 14A).

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