Designing new drug candidates as inhibitors against wild and mutant type neuraminidases: molecular docking, molecular dynamics and binding free energy calculations

Influenza virus is the cause of the death of millions of people with about 3–4 pandemics every hundred years in history. It also turns into a seasonal disease, bringing about approximately 5–15% of the population to be infected and 290,000–650,000 people to die every year. These numbers reveal that it is necessary to be on the alert to work towards influenza in order to protect public health. There are FDA-approved antiviral drugs such as oseltamivir and zanamivir recommended by the World Center for Disease Prevention. However, after the recent outbreaks such as bird flu and swine flu, increasing studies have shown that the flu virus has gained resistance to these drugs. So, there is an urgent need to find new drugs effective against this virus. This study aims to investigate new drug candidates targeting neuraminidase (NA) for the treatment of influenza by using computer aided drug design approaches. They involve virtual scanning, de novo design, rational design, docking, MD, MMGB/PBSA. The investigation includes H1N1, H5N1, H2N2 and H3N2 neuraminidase proteins and their mutant variants possessing resistance to FDA-approved drugs. Virtual screening consists of approximately 30 thousand molecules while de novo and rational designs produced over a hundred molecules. These approaches produced three lead molecules with binding energies for both non-mutant (-34.84, −59.99 and −60.66 kcal/mol) and mutant (-40.40, −58.93, −76.19 kcal/mol) H2N2 NA calculated by MM-PBSA compared with those of oseltamivir −25.64 and −18.40 respectively. The results offer new drug candidates against influenza infection. Communicated by Ramaswamy H. Sarma