Study on molecular mechanism and 3D-QSAR of influenza neuraminidase inhibitors

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Abstract

Neuraminidase (NA) is a critical enzyme of the influenza virus and many inhibitors targeting to this enzyme are quite efficient and encouraging as anti-influenza agents. In this paper the binding model of five series of inhibitors to NA was examined using molecular simulation method. The resulted conformation and orientation of the compounds were directly put into CoMSIA study. The most significant amino acid residues at binding sites and the requirement for features of substituents were applied to direct design of new inhibitors. The robust QSAR model and its three-dimensional contour map provided guidelines to building novel compounds with new scaffold and for structural optimization of current molecules.

The binding mode of a series of neuraminidase (NA) inhibitors with various scaffold structures were investigated by application of molecular simulation methods. A robust QSAR model was obtained using CoMSIA method. The resulting information provided a significant guide to further modification of NA inhibitors.

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Introduction

Influenza is a respiratory infection associated with significant morbidity in the general population and mortality in elderly and high-risk patients. Current therapeutic measures have only provided limited control. Vaccines are frequently ineffective because influenza viral antigens mutate at rapid rate in forms of antigenic drift and shift.1 Other options for the therapeutic treatment of influenza are limited to amantadine and rimantadine, which are of restricted usefulness because of the insensitivity to influenza virus B, unwanted side effects, and resistance problems. New influenza drugs with broad-spectrum activity are needed.

The life cycle of the influenza virus provides several potential molecular targets for drug innovation. Among those potential targets, neuraminidase (NA) appears to be particularly attractive. NA is one of two glycoproteins expressed on the surface of virus and is responsible for viral release from infected cells and viral transport through the mucus in the respiratory tract.2 NA also destroys hemagglutinin receptor on host cells, thus allowing the emergence of progeny virus particles from infected cells. Therefore, compounds that inhibit NA can protect the host from viral infection and retard its propagation. The catalytic active site of NA is located in a concave cavity on the protein surface, and the residues lining the active site of NA are highly conserved across all influenza A and B virus strains,3 rendering board-spectrum anti-influenza agents possible.

Structure-based drug design methods have played a critical role in the discovery of NA inhibitors. By exploiting the crystal structure of NA–inhibitors complexes, many compounds were successfully optimized and modified based on the characters of charge and shape in binding site, such as Zanamivir launched in 1999.4 Rational pharmacophore models of inhibitors like the airplane model5 and the sketch map of interaction features for strong inhibitor and the binding site6 were derived for drug design. Many computational methods were applied to research the correlations between binding energy of inhibitors to NA and their inhibitory activity. However, most of these studies were confined to the same scaffold compounds and hence the predictable ability was very restricted.

Hundreds of NA inhibitors and a large body of inhibitory activity data have recently been reported.7 The purpose of this paper is to examine binding features of inhibitors bearing various scaffolds in the active pocket of NA enzyme, to analyze the interaction strength of different substituents with amino acids residues of binding sites, and to propose a presumable model for designing new compounds based on the knowledge of the information of the enzyme and inhibitor structures. Methodologically a docking operation based on genetic algorithm and molecular mechanics simulation was performed to account for the experimental data. Meantime, Comparative molecular similarity analysis (CoMSIA),8 one of classical QSAR methods, was carried out to reveal the accordance of contour map with the distribution of amino acid residues in binding site of NA.

Section snippets

Selection of compounds

The design and synthesis of NA inhibitors have been concentrated on the sialic acid analogues and derivatives, among which Zanamivir and Oseltamivir phosphate have been marketed as an antifluenza nasal spray (Relenza) and orally administered NA inhibitor, respectively.9 The emergence of carbocyclic and heterocyclic counterpart greatly encouraged medicinal chemists since these potent NA inhibitors are chemically more accessible. Recently a cyclopentane derivative, Peramivir, has been reported

The binding features of inhibitors with various scaffolds and different substituents to NA enzyme possess an evident similarity

A scrutiny of the crystal structures revealed that the NA complexed with an inhibitor (including Zanamivir and benzoic acid derivative BCX-140) showed a nearly identical three-dimensional structure. Several other potential inhibitors were reported to orient almost in the same way in the active pocket as Zanamivir by application of soaking crystal method.24, 25 Thus in the present study the crystal structure of NA–Zanamivir complex (PDB code 1nnc) was assigned to the investigation of molecular

Conclusion

The application of Autodock and MMFF procedure provided an efficient approach to correctly orienting and positioning each of 37 inhibitors in the binding pocket of NA. Combining the amino acids residue distribution in binding pocket and contour maps from PLS analysis, some explanation could be given for the variation in the activities of current structures, hence new inhibitors with potentially high activity could be designed. To maintain the inhibitory activity a positive group at C4-position

Acknowledgements

We are grateful to Dr. Ting Wang and Prof. Rebecca Wade (European Molecular Biology Laboratory) for interesting discussion. We also thank Dr. Y. S. Babu of BioCryst Pharmaceuticals, Inc. for providing the crystal structures of six neuraminidase inhibitor complexes.

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