Free Energy Calculations and Binding Analysis of Two Potential Anti- Influenza Drugs with Polymerase Basic Protein-2 (PB2)

nfluenza viruses cause a significant level of morbidity and mortality in the population every year. Their resistance to current anti-influenza drugs increases the difficulty of flu treatment. Thus, development of new anti-influenza drugs is necessary in regards of prevent the tragedy of influenza pandemic. The Polymerase basic protein 2 (PB2) subunit of influenza virus RNA polymerase is one of potential targets for new drugs because the binding of PB2 with the 5' cap of the host pre-mRNAs is the initial step of the virus' protein synthesis. In this study, we compared the binding potency of PB2 cap binding domain with two small molecules, i.e., RO and PPT28, with that of PB2 with cap analog m7GTP. The calculated binding energies showed that RO and PPT28 had higher binding affinity with PB2. Further interaction analysis showed that the important parts for binding were the five- and six-member heterocyclic rings (the 6/5-member rings) of small molecules, as well as the hydrophobic parts of RO and PPT28 which had good interactions with the hydrophobic residues in the binding cavity. Thus, RO and PPT28 are two potential anti-influenza drugs targeted PB2, which may inhibit the growth of influenza virus by competitively binding with the cap structure binding domain of PB2. Keywords: Anti-influenza drug, molecular docking, molecular dynamic simulation, MM/GBSA, PB2, free energy calculation, PPT28, m7GTP, RNA polymerase, GALL, NPT, AMBER package, RMSDAnti-influenza drug, molecular docking, molecular dynamic simulation, MM/GBSA, PB2, free energy calculation, PPT28, m7GTP, RNA polymerase, GALL, NPT, AMBER package, RMSD