Docking and Molecular Dynamics Simulations in Potential Drugs Discovery: An Application to Influenza Virus M2 Protein

Molecular docking is a common method for searching new potential drugs. Improvement of the results of docking can be achieved by different ways-one of them is molecular dynamics simulations of protein-ligand complexes. As a model for our research we chose M2 membrane protein from influenza virus. M2 protein is a high selective tetrameric pH-gated proton channel. It was previously shown that Omeprazole Family Compounds (OFC) block the "proton pump", though we hypothesized further that they could interfere with the mechanism of fusion of the virus envelope and endosomal membrane, thereby hindering the M2 proton pump mechanism of influenza viruses. We carried out a Molecular Dynamics (MD) simulation in order to predict constant of binding for OFC. We simulated M2 Protein (PDB code 3C9J) in complex with its ligands: Amantadine, rimantadine as positive controls and omeprazole as putative ligand. We made use of molecular docking as well as the thermodynamic integration method to estimate binding free energies of the ligands. We demonstrate that the thermodynamic integration method predicts free energies of ligand binding better than molecular docking while embedding of M2 protein in a membrane further improves the calculated free energy values. Free energy calculations imply omeprazole as a potent anti-viral drug.