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Computer-Based De Novo Designs of Tripeptides as Novel Neuraminidase Inhibitors
Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin 150040, China
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
* Authors to whom correspondence should be addressed.
Received: 20 October 2010; in revised form: 12 November 2010 / Accepted: 18 November 2010 / Published: 1 December 2010
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 (NH3+) 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.
Keywords: docking; influenza; neuraminidase inhibitors; tripeptides; H-bonds; de novo drug designs
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Cite This Article
MDPI and ACS Style
Yang, Z.; Yang, G.; Zu, Y.; Fu, Y.; Zhou, L. Computer-Based De Novo Designs of Tripeptides as Novel Neuraminidase Inhibitors. Int. J. Mol. Sci. 2010, 11, 4932-4951.
Yang Z, Yang G, Zu Y, Fu Y, Zhou L. Computer-Based De Novo Designs of Tripeptides as Novel Neuraminidase Inhibitors. International Journal of Molecular Sciences. 2010; 11(12):4932-4951.
Yang, Zhiwei; Yang, Gang; Zu, Yuangang; Fu, Yujie; Zhou, Lijun. 2010. "Computer-Based De Novo Designs of Tripeptides as Novel Neuraminidase Inhibitors." Int. J. Mol. Sci. 11, no. 12: 4932-4951.