Free Energy Calculations And Binding Analysis Of Two Potential Anti-influenza Drugs With Polymerase Basic Protein-2 (PB2)

Influenza viruses cause a significant level of morbidity and mortality in the population every year. Nowadays, two classes of drugs are widely used for the treatment and prevention of infection. One class is known as adamantanes consisting of amantadine and rimantadine and the other class is known as neuraminidase inhibitors consisting of oseltamivir and zanamivir. Unfortunately, resistant viruses are rapidly selected in patients treated with these drugs. The development of new anti-influenza drugs is a good way to solve the problem and to prevent the tragedy of influenza pandemic. The influenza virus polymerase complex plays an important role in virus'replication, and the binding of the polymerase PB2 subunit with the 5'cap of the host pre-mRNAs is the initial step of the virus'protein synthesis. That's why we chose PB2 as the target of our experiment. We analyzed the binding potency of PB2 cap structure binding domain with two small molecules, i.e., RO and PPT28, comparing with that of PB2 with cap analog m7GTP by the methods of Molecular Docking and Molecular Dynamics Simulation. The binding energies calculated by MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) showed that RO and PPT28 have better binding affinity with PB2. And the further interaction analysis showed that the important parts for binding were the 6-5-member rings of small molecules, as well as the hydrophobic parts of RO and PPT28 which have good interactions with the hydrophobic residues in the binding cavity.5'cap of the host mRNAs is also important for the host mRNAs translation. The binding of Eukaryotic initiation factor 4E (eIF4E) with 5'cap of the host mRNAs sparks the assembly of ribosome larger and smaller subunit and then starts the translation of the host mRNAs. The way the cap structure binds to PB2 and eIF4E is similar. To make sure that RO and PPT28 will not block the translation of the host mRNAs, we docked m7GTP, RO and PPT28 into eIF4E respectively. The results show that RO and PPT28 can't bind eIF4E well.Thus, RO and PPT28 are potential new anti-influenza drugs targeted PB2, which may inhibit the growth of influenza virus by competitively binding with the cap structure binding domain of PB2 but at the same time will not prevent the translation of the host mRNAs. Finally, we use RO and PPT28 respectively as query molecules to do database searching. Molecular dockings were undertaken between the selected out similar molecules and PB2, eIF4E respectively. And we have found 3 molecules that also have the potential to be new anti-influenza drugs targeted PB2.