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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

Views of the binding modes of the NA active-site residues with (a) FHV and (b) YRV. Key residues are represented by stick models. Tripeptides are represented by ball and stick models. The important H-bonds are labeled as dashed black lines.
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f5-ijms-11-04932: Views of the binding modes of the NA active-site residues with (a) FHV and (b) YRV. Key residues are represented by stick models. Tripeptides are represented by ball and stick models. The important H-bonds are labeled as dashed black lines.

Mentions: In order to clarify the roles of the Arg and Phe portions in the tripeptide FRV, another two tripeptides FHV and YRV were designed as NA inhibitors. The interaction energy (Einter) of FHV with NA is calculated to be −254.00 kcal mol−1 (Figure 3). As a result of the disappearance of the Arg portion (R→H mutation), the interaction energy (Einter) of FHV is about 36 kcal mol−1 lower than that of FRV. The His portion of FHV does not form any H-bond with the active-site residues and rather moves out of the active-site pocket (Figure 5a). In the meantime, the charge transfers of FHV with residues Glu119, Asp151, Glu227, Glu276 and Glu277 decrease, in contrast to the case of FRV, especially residues Glu276 and Glu277 (Tables S1 and S2). Accordingly, the Arg portion is crucial to FRV and responsible for the lower interaction energy of FHV.


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)

Views of the binding modes of the NA active-site residues with (a) FHV and (b) YRV. Key residues are represented by stick models. Tripeptides are represented by ball and stick models. The important H-bonds are labeled as dashed black lines.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5-ijms-11-04932: Views of the binding modes of the NA active-site residues with (a) FHV and (b) YRV. Key residues are represented by stick models. Tripeptides are represented by ball and stick models. The important H-bonds are labeled as dashed black lines.
Mentions: In order to clarify the roles of the Arg and Phe portions in the tripeptide FRV, another two tripeptides FHV and YRV were designed as NA inhibitors. The interaction energy (Einter) of FHV with NA is calculated to be −254.00 kcal mol−1 (Figure 3). As a result of the disappearance of the Arg portion (R→H mutation), the interaction energy (Einter) of FHV is about 36 kcal mol−1 lower than that of FRV. The His portion of FHV does not form any H-bond with the active-site residues and rather moves out of the active-site pocket (Figure 5a). In the meantime, the charge transfers of FHV with residues Glu119, Asp151, Glu227, Glu276 and Glu277 decrease, in contrast to the case of FRV, especially residues Glu276 and Glu277 (Tables S1 and S2). Accordingly, the Arg portion is crucial to FRV and responsible for the lower interaction energy of FHV.

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