Abstract
The growing resistance of the influenza virus to widely used competitive neuraminidase inhibitors occupying the active site of the enzyme requires the development of bifunctional compounds that can simultaneously interact with other regulatory sites on the protein surface. When developing such an inhibitor and combining structural fragments that could be located in the sialic acid cavity of the active site and the adjacent 430-cavity, it is necessary to select a suitable linker not only for connecting the fragments, but also to ensure effective interactions with the unique arginine triad Arg118-Arg292-Arg371 of neuraminidase. Using molecular modeling, we have demonstrated the usefulness of the sulfonamide group in the linker design and the potential advantage of this functional group over other isosteric analogues.
Highlights
Among the known influenza viruses, the most dangerous is type A, which affects approximately 1 billion people annually and causes periodic pandemics [1,2,3]
In the period 2008–2009, there was a dramatic increase in the resistance of the H1N1 virus to oseltamivir due to the H275Y mutation in the sialic acid binding site [12,13]
We investigated the possibility of creating a suitable linker based on the sulfonamide group, the choice ofsurface which was due towith several factors. residues
Summary
Among the known influenza viruses, the most dangerous is type A, which affects approximately 1 billion people annually and causes periodic pandemics [1,2,3]. Oseltamivir (9) [7,8,9] These molecules compete for the sialic acid binding site formed by a number of charged residues as well as by the side chain of the catalytic residue Tyr406, and thereby suppress the enzyme activity [10,11]. In the period 2008–2009, there was a dramatic increase in the resistance of the H1N1 virus to oseltamivir due to the H275Y mutation in the sialic acid binding site [12,13]. Other substitutions reducing the inhibitory effect have been reported: E119A (H5N1) [14], Q136K/R (H1N1), R292K (H3N2) [15,16] This indicates the need to develop new inhibitors that could bind to other sites on the protein surface and suppress neuraminidase activity
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