Introduction of drugs puts an evolutionary pressure on viruses and makes the viral proteins evolve. On the other hand, the change in the protein structure should be compatible with the protein function. The degree of the protein sequence conservativity is thus a measure of the structural importance of a particular region on the protein surface. Certain binding sites are evolving and mutate often, certain are not. Finding the most conservative fractions of a target protein sequence can help identify important and druggable binding sites for inhibitors search, find drugs with the least potential for drug resistance development.

Below we provide an analysis of H5N1 neuromidase protein surface next to the tamiflu binding region. The Figure shows the level of protein structure conservation, red portions corresponds to the most conservative residues. A small yellow patch of the pocket has evolved since 1990 and gave way to develop tamiflu resistance.

The analysis shows that in spite of a lot of pressure from the drug application, the virus was not able to change the red part of the pocket. Future drugs should target the binding sites with the least mutable residues.

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