Computer aided drug design supported anti-influenza neuraminidase drug design

Influenza, commonly known as flu, is a contagious and deadly disease caused by influenza viruses. Influenza virus has caused the death of millions of people by creating about 3-4 pandemics and 4-5 epidemics every hundred years. This virus, which mutates easily and adapts to many hosts, also makes seasonal disease, causing about 5-15% of the population to be infected, 3-5 million people to suffer from severe illness, and 290.000-650.000 people to die every year. These numbers reveal the necessity of being on the alert and working towards influenza at all times in order to protect public health. There are FDA-approved antiviral drugs Tamiflu®) (Oseltamivir -OSC), Relenza™ (Zanamivir -ZMR) developed against influenza. However, after the recent epidemics such as bird flu and swine flu, increased studies have shown that the flu virus has acquired resistance to these drugs. In this study, we tried to find molecules with the potential to be a neuraminidase (one of the surface glycoproteins of the influenza virus) inhibitor, by using computer aided drug design methods (virtual scanning, denovo design, rational design, dock, MD, MM-PB(GB)/SA). For this purpose, we prepared H1N1, H5N1, H2N2 and H3N2 neuraminidase proteins, one of the influenza A virus subtypes that caused pandemics in humans in the last century, and their mutant variants that developed resistance to FDA-approved drugs (Oseltamivir (OSC) and zanamivir (ZMR)) and we used these eight proteins as receptors in calculations. More than seven thousand molecules determined by virtual scanning or more than a hundred molecules designed with denovo design and rational design were tested against these receptors to test potential NAI efficacy. According to Dock scores, MD calculations and MM-PB(GB)/SA scores, it was found that especially vo1, f01 and r84 coded molecules gave successful results in all proteins. For example, in the binding free energy comparisons calculated with MM-PB(GB)/SA, while the binding free energy for the non-mutant 3TIA protein complexes with OSC was -25,64 kcal/mol, this energy was found to be -34,84; -60,66; -59,99 kcal/mol for complexes with r84, f01, vo1 molecules respectively. Likewise, while the binding free energy for the mutant 3TIA protein complexes with OSC was -18,40 kcal/mol, this energy was found to be -40.40; -58,93; -76,19 kcal/mol for mutant 3TIA protein complexes with r84, f01, vo1 molecules, respectively. In this study, the part about the rationally designed r84 molecule is also explained in detail.