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Computer-based de novo designs of tripeptides as novel neuraminidase inhibitors.

Yang Z, Yang G, Zu Y, Fu Y, Zhou L - Int J Mol Sci (2010)

Bottom Line: Their interactions with NA are studied and compared with each other, using flexible docking and molecular dynamics simulations.The various composed tripeptides have respective binding specificities and their interaction energies with NA decrease in the order of FRI > FRV > FRT > FHV > FRS > FRG > YRV (letters corresponding to amino acid code).Experimental efforts are expected in order to actualize the tripeptides as potent NA inhibitors in the near future.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin 150040, China; E-Mails: yzws-123@163.com (Z.Y.); fuyujie1967@yahoo.com.cn (Y.F.); zlj_1008@yahoo.com.cn (L.Z.).

ABSTRACT
The latest influenza A (H1N1) pandemic attracted worldwide attention and called for the urgent development of novel antiviral drugs. Here, seven tripeptides are designed and explored as neuraminidase (NA) inhibitors on the structural basis of known inhibitors. Their interactions with NA are studied and compared with each other, using flexible docking and molecular dynamics simulations. The various composed tripeptides have respective binding specificities and their interaction energies with NA decrease in the order of FRI > FRV > FRT > FHV > FRS > FRG > YRV (letters corresponding to amino acid code). The Arg and Phe portions of the tripeptides play important roles during the binding process: Arg has strong electrostatic interactions with the key residues Asp151, Glu119, Glu227 and Glu277, whereas Phe fits well in the hydrophobic cave within the NA active site. Owing to the introduction of hydrophobic property, the interaction energies of FRV and FRI are larger; in particular, FRI demonstrates the best binding quality and shows potential as a lead compound. In addition, the influence of the chemical states of the terminal amino acids are clarified: it is revealed that the charged states of the N-terminus (NH(3) (+)) and C-terminus (COO(-)) are crucial for the tripeptide inhibitory activities and longer peptides may not be appropriate. In addition, the medium inhibiting activity by acetylation of the N-terminus indicates the possible chemical modifications of FRI. Experimental efforts are expected in order to actualize the tripeptides as potent NA inhibitors in the near future.

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Related in: MedlinePlus

The electrostatic (Eele, blue sparse area) and total interaction energies (Einter) between NA protein and various tripeptides.
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f3-ijms-11-04932: The electrostatic (Eele, blue sparse area) and total interaction energies (Einter) between NA protein and various tripeptides.

Mentions: The interaction energy (Einter) of FRG with NA is calculated at −249.83 kcal mol−1, where the electrostatic rather than vdW interactions are found to play a dominant role (Figure 3). As Figure 4a shows, the carboxyl group of FRG has three H-bonds with the positively charged guanidino group of residue Arg152. The guanidino group of FRG forms ionic interactions with the negatively charged carboxyl groups of residues Glu119, Asp151 and Glu227, with one H-bond formed with each residue. The electrostatic contributions (Eele) of residues Glu119, Asp151, Arg152 and Glu227 amount to −92.93, −132.39, −37.21 and −63.39 kcal mol−1, respectively (Table S1). Nonetheless, the benzene group of FRG somewhat flips out from the NA active site. The lack of sidechains in Gly (H atoms) does not match with the hydrophobic portion of the NA active site. Accordingly, the C-terminus of FRG (Gly) is improved by the G→V mutation.


Computer-based de novo designs of tripeptides as novel neuraminidase inhibitors.

Yang Z, Yang G, Zu Y, Fu Y, Zhou L - Int J Mol Sci (2010)

The electrostatic (Eele, blue sparse area) and total interaction energies (Einter) between NA protein and various tripeptides.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3100827&req=5

f3-ijms-11-04932: The electrostatic (Eele, blue sparse area) and total interaction energies (Einter) between NA protein and various tripeptides.
Mentions: The interaction energy (Einter) of FRG with NA is calculated at −249.83 kcal mol−1, where the electrostatic rather than vdW interactions are found to play a dominant role (Figure 3). As Figure 4a shows, the carboxyl group of FRG has three H-bonds with the positively charged guanidino group of residue Arg152. The guanidino group of FRG forms ionic interactions with the negatively charged carboxyl groups of residues Glu119, Asp151 and Glu227, with one H-bond formed with each residue. The electrostatic contributions (Eele) of residues Glu119, Asp151, Arg152 and Glu227 amount to −92.93, −132.39, −37.21 and −63.39 kcal mol−1, respectively (Table S1). Nonetheless, the benzene group of FRG somewhat flips out from the NA active site. The lack of sidechains in Gly (H atoms) does not match with the hydrophobic portion of the NA active site. Accordingly, the C-terminus of FRG (Gly) is improved by the G→V mutation.

Bottom Line: Their interactions with NA are studied and compared with each other, using flexible docking and molecular dynamics simulations.The various composed tripeptides have respective binding specificities and their interaction energies with NA decrease in the order of FRI > FRV > FRT > FHV > FRS > FRG > YRV (letters corresponding to amino acid code).Experimental efforts are expected in order to actualize the tripeptides as potent NA inhibitors in the near future.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin 150040, China; E-Mails: yzws-123@163.com (Z.Y.); fuyujie1967@yahoo.com.cn (Y.F.); zlj_1008@yahoo.com.cn (L.Z.).

ABSTRACT
The latest influenza A (H1N1) pandemic attracted worldwide attention and called for the urgent development of novel antiviral drugs. Here, seven tripeptides are designed and explored as neuraminidase (NA) inhibitors on the structural basis of known inhibitors. Their interactions with NA are studied and compared with each other, using flexible docking and molecular dynamics simulations. The various composed tripeptides have respective binding specificities and their interaction energies with NA decrease in the order of FRI > FRV > FRT > FHV > FRS > FRG > YRV (letters corresponding to amino acid code). The Arg and Phe portions of the tripeptides play important roles during the binding process: Arg has strong electrostatic interactions with the key residues Asp151, Glu119, Glu227 and Glu277, whereas Phe fits well in the hydrophobic cave within the NA active site. Owing to the introduction of hydrophobic property, the interaction energies of FRV and FRI are larger; in particular, FRI demonstrates the best binding quality and shows potential as a lead compound. In addition, the influence of the chemical states of the terminal amino acids are clarified: it is revealed that the charged states of the N-terminus (NH(3) (+)) and C-terminus (COO(-)) are crucial for the tripeptide inhibitory activities and longer peptides may not be appropriate. In addition, the medium inhibiting activity by acetylation of the N-terminus indicates the possible chemical modifications of FRI. Experimental efforts are expected in order to actualize the tripeptides as potent NA inhibitors in the near future.

Show MeSH
Related in: MedlinePlus