Computer-Based De Novo Designs of Tripeptides as Novel Neuraminidase Inhibitors

Zhiwei Yang,Yuangang Zu,Yujie Fu,Lijun Zhou,Gang Yang

doi:10.3390/ijms11124932

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.

Highlights

At present, influenza is probably the most serious pandemic threat to human health [1,2,3]
A series of tripeptides were explored as potential neuraminidase (NA) inhibitors
Their interactions with the NA protein were studied by flexible docking and molecular dynamics (MD)

Summary

Introduction

Influenza is probably the most serious pandemic threat to human health [1,2,3]. The influenza virus causes severe morbidity and mortality in poultry as a result of co-infection with other pathogens [4]. Zanamivir and oseltamivir (known as Tamiflu) are two known anti-influenza drugs that have been widely used in the chemoprophylaxis and treatment of influenza and stockpiled in preparation for pandemic outbreak [4,5,6,7]. It becomes very urgent to develop novel and efficient anti-influenza drugs in order to prevent and treat influenza infections [2]. Neuraminidase (NA) is a major surface glycoprotein of influenza virus that plays a crucial role in the release of new viral particles [11]. The inhibition of NA will delay the release of progeny virions from infected host cell and allow the host immune systems sufficient time to clear them [12]. The active sites of NAs are highly conserved across different sub-types of influenza viruses, especially for

Methods

Results

Conclusion