Análise molecular da mutação HIS275TIR isolada na Neuraminidase do H1N1 resistente ao oseltamivir

Abstract

The latest influenza pandemic occurred in the year 2009, caused by the strain of influenza A (H1N1), and popularly known as influenza A or swine flu, generated concern to the global health agencies. With a symptomatic picture that includes fever, cough, throat inflammation in most cases, some patients, mainly immunosuppressed, that can to present complications that evolve to death. Transmission of the virus takes place through contact between person to person and its mechanism of infection occurs from the two surface glycoproteins, hemagglutinin and neuraminidase. The hemagglutinin acts by binding to the sialic acid receptors favoring the entry of the virus into the target cells and the neuraminidase cleaves the receptor cells of sialic acid residues, where the new viral particles are binding. Through this breakdown there will be release of the new particles that through hemagglutinin will attack new cells. Based on these, drugs were developed in an attempt to inhibit the action of neuraminidase, so called neuraminidase inhibitors that interfere in the release of these new viral particles avoiding the spread of infection in the respiratory tract. Among the inhibitors, oseltamivir is the drug of choice for prophylaxis and treatment of influenza A, but reports of resistance to this drug have been described, which has caused concern in health professionals and rulers. The HIS275TIR mutation is most commonly found, where histidine is replaced by a tyrosine, promoting a series of conformational changes that decrease the affinity of the drug for the virus causing resistance. Based on crystallographic data and computational simulation, we calculated the interaction energy of the wild neuraminidase and the presence of the HIS275TIR mutation bonded to oseltamivir using the Functional Density Theory (DFT) and the Molecular Fractionation with Conjugated Caps (MFCC). We obtained 115 interaction residues for the wild neuraminidase (4B7R crystal) and 109 interaction residues for the crystal with the mutant neuraminidase (3CL0). The results were evaluated according to the relevance of the energy values for repulsive energies and attractive energies. The energetic calculations confirmed the reduction of the affinity of the strain containing the HIS275TIR mutation and highlighted the energy importance of the active site of the neuraminidase, showing that the main energy residues are found in it becoming a target for obtaining new drugs due to its conservation. The changes caused by the substitution of the amino acid histidine for a tyrosine led to a series of conformational changes in the neighboring amino acids that provoked electrostatic changes resulting in the resistance to the drug. From this study, it will be possible to know better the molecular interactions of the mutant neuraminidase and subsequently to project new drugs designs to be elaborated and become more efficient in the interaction with the mutant strains of this virus.