EFFECT OF H1N1 NEURAMINIDASE MUTATIONS IN THE BINDING MODE OF KNOWN ANTIVIRAL COMPOUNDS

ESTEBAN VEGA-HISSI; GUTIERREZ LUCAS JOEL; ANDRADA MATIAS; ESTRADA MARIO; GARRO JUAN MARTINEZ

Conferencia; 13th Latin American Conference on Physical Organic Chemistry; 2015

The pandemic nature of the influenza viruses and its ability to rapidly mutate present a serious public healthconcern and emphasize the importance of developing new and effective anti-influenza drugs.There are two main glycoproteins on the surface of influenza virus particles, hemagglutinin (HA) andneuraminidase (NA), which are both targets of the neutralizing antibodies immune response. Due to its essentialrole in limiting the progression of influenza virus infection in the host and its relatively well-conserved active sites,NA has become an attractive target for structure-based antiviral drug development.The catalytic site of the NA is constituted of eight functional residues, surrounded by eleven framework residuesimplicated in the stabilization of the active site structure. These residues are conserved in all influenza viruses.Influenza viruses with reduced sensitivity to NA inhibitors such as oseltamivir, zanamivir and peramivir, typicallycontain mutations in the enzyme which directly or indirectly alter the shape of the NA catalytic site, thus reducingthe inhibitor binding ability.We employed a hybrid Quantum Mechanics-Molecular Mechanical (QM/MM) method together with a QTAIM(Quantum Theory of Atoms In Molecules) analysis to investigate in details the binding of NA inhibitors to NA wildtype and NA bearing specific mutations.Our computational calculations revealed that the mutations in the influenza neuraminidase lead to loss of specificstabilizing interactions of the inhibitor-NA complex. Although new energy contributions to the binding of theinhibitors to NA mutants appeared, they were not able to compensate the loss of the energies produced by otherresidues.These results also showed that from relatively simple molecular modeling techniques it is possible to explain thebinding behavior of inhibitors that have a similar affinity for an enzyme and its mutant versions.