Some novel insights into the binding of oseltamivir and zanamivir to H5N1 and N9 influenza virus neuraminidases: A homology modeling and flexible docking study

Abstract

In the context of the recent pandemic threat by the worldwide spread of H5N1 avian influenza, novel insights into the mechanism of ligand binding and interaction between various inhibitors (zanamivir -ZMV, oseltamivir -OTV, 2,3-didehydro-2-deoxy-N-acetylneuraminic acid -DANA, peramivir -PMV) and neuraminidases (NA) are of vital importance for the structure-based design of new anti-viral drugs. To address this issue, three-dimensional models of H5N1-NA and N9-NA were generated by homology modeling. Traditional residues within the active site throughout the family of NA protein structures were found to be highly conserved in H5N1-NA. A subtle variation between lipophilic and hydrophilic environments in H5N1-NA with respect to N9-NA was observed, thus shedding more light on the high resistance of some H5N1 strains to various NA inhibitors. Based on these models, an ArgusLab4/AScore flexible docking study was performed. The conformational differences between OTV bound to H5N1-NA and OTV bound to N9-NA were structurally identified and quantified. A slight difference of less than 1 kcal mol -1 between the OTV-N9 and OTV-N1 binding free energies is in agreement with the experimentally predicted free energy difference. The conformational differences between ZMV and OTV bound to either H5N1-NA or N9-NA were structurally identified. The binding free energies of the ZMV complexes, being slightly higher than those of OTV, are not in agreement with what was previously proposed using homology modeling. The differences between ZMV and OTV are suggested to be ascribed to the presence/absence of Asn166 in the active cavity of ZMV/OTV in H5N1-NA, and to the presence/absence of Ser165 in the binding site of ZMV/OTV in N9-NA. The charge distribution was evaluated using the semi-empirical AM1 method. The trends of the AM1 charges of the ZMV and OTV side chains in the complexes deviate from those previously reported.

Prediction of Single Point Mutations in Human Coronavirus and Their Effects on Binding to 9-O-Acetylated Sialic Acid and Hidroxychloroquine

“…The AScore/ShapeDock protocol is fast, reproducible and formally explores all energy minima. 23 This particular protocol was shown to be very consistent for docking ligands into the crystal structures of viral proteins, [24][25][26][27][28] while the calculated binding free energies were well-correlated with the experimental inhibitory concentrations. 26…”

Prediction of Mutation Positions in H5N1 Neuraminidases From Influenza A Virus by Means of Neural Network

“…[12][13][14][15][16][17]20 In general, the amino acids in these positions are glutamic acid, arginine, and histidine, of which both arginine and histidine have the highest ratio of future composition versus current one among Table 3 and would-be-mutated amino acids related to isoleucine at positions 30, and proline at position 400 based on the translation probability between RNA codons and mutated amino acids (upper panel). 20 types of amino acids in H5N1 neuraminidases, suggesting a piece of rationale for their frequent mutations.…”

Interaction of Chalcones With Ct-Dna by Spectrophotometric Analysis and Theoreticalsimulations

“…21 Candidate conformations of Chalcones interacting to their target structures, the DNA complex, were proposed using Arguslab. 22,23 Here, docking was carried out with a set of Chalcones. (Figure 1) …”