Limits...
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.

Show MeSH

Related in: MedlinePlus

(A) The superposition of 1G65_K template (green ribbon) and the β5 subunit of human proteasome (red ribbon) from homology modeling; (B) The enlargement of the superposition structure of the active site with ligand EPX displayed as balls and sticks. The residues from the template protein and the homology modeling protein are highlighted in green and red colors, respectively. The same residues are labeled in blue color, while the different residues between them are labeled in their own color.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7-ijms-12-01807: (A) The superposition of 1G65_K template (green ribbon) and the β5 subunit of human proteasome (red ribbon) from homology modeling; (B) The enlargement of the superposition structure of the active site with ligand EPX displayed as balls and sticks. The residues from the template protein and the homology modeling protein are highlighted in green and red colors, respectively. The same residues are labeled in blue color, while the different residues between them are labeled in their own color.

Mentions: In the present work, the whole sequence identity between the target (β5 subunit of human proteasome) and the template protein (PDB code: 1G65_K) is 68%. Except the precursor amino acid sequence (amino acids 1–59), the functional sequence identity is 71% (amino acids 60–247). Thus, with a high level of sequence identity, the appreciated template 1G65 can be used to construct a reliable 3D structure and guarantee the quality of homology model. Since an N-terminal threonine (Thr) residue is very important for the catalytic activity (Thr60 in human), we added a Thr60 to the N-terminal of the modeling protein which we did not modeled by homology modeling. The superposition of the model to template is shown in Figure 7, indicating that the overall conformation of the modeling target is very similar to the template with a root-mean-square deviation (RMSD) of 1.423 Å (<2 Å). Furthermore, we carefully analyzed the alignment in the critical residues of the binding site and found that almost all important amino acids (such as Asp76, Thr80, Lys92, Gly106, Ser189 and Ser229) overlapped well in 3D space for the two structures (The amino-acid numbering in the sequences of template and modeling structures starts at the N-terminal catalytic threonines (Thr2 and Thr60)).


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) The superposition of 1G65_K template (green ribbon) and the β5 subunit of human proteasome (red ribbon) from homology modeling; (B) The enlargement of the superposition structure of the active site with ligand EPX displayed as balls and sticks. The residues from the template protein and the homology modeling protein are highlighted in green and red colors, respectively. The same residues are labeled in blue color, while the different residues between them are labeled in their own color.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7-ijms-12-01807: (A) The superposition of 1G65_K template (green ribbon) and the β5 subunit of human proteasome (red ribbon) from homology modeling; (B) The enlargement of the superposition structure of the active site with ligand EPX displayed as balls and sticks. The residues from the template protein and the homology modeling protein are highlighted in green and red colors, respectively. The same residues are labeled in blue color, while the different residues between them are labeled in their own color.
Mentions: In the present work, the whole sequence identity between the target (β5 subunit of human proteasome) and the template protein (PDB code: 1G65_K) is 68%. Except the precursor amino acid sequence (amino acids 1–59), the functional sequence identity is 71% (amino acids 60–247). Thus, with a high level of sequence identity, the appreciated template 1G65 can be used to construct a reliable 3D structure and guarantee the quality of homology model. Since an N-terminal threonine (Thr) residue is very important for the catalytic activity (Thr60 in human), we added a Thr60 to the N-terminal of the modeling protein which we did not modeled by homology modeling. The superposition of the model to template is shown in Figure 7, indicating that the overall conformation of the modeling target is very similar to the template with a root-mean-square deviation (RMSD) of 1.423 Å (<2 Å). Furthermore, we carefully analyzed the alignment in the critical residues of the binding site and found that almost all important amino acids (such as Asp76, Thr80, Lys92, Gly106, Ser189 and Ser229) overlapped well in 3D space for the two structures (The amino-acid numbering in the sequences of template and modeling structures starts at the N-terminal catalytic threonines (Thr2 and Thr60)).

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