Influenza A virus (IAV) continues to represent a significant threat to public health each year. The AM2 transmembrane protein of IAV is one of the main targets for antiviral treatment, as it plays a crucial role in the early stages of the viral replication cycle. However, the established inhibitors of the AM2 proton channel, amantadine and rimantadine, have proven ineffective due to the widespread viral mutations, which has increased the need for the discovery of novel potential inhibitors. The aim of this master's thesis was to identify new potential inhibitors of the AM2 proton channel of IAV and to evaluate their stability and binding free energy using computational approaches, including molecular docking, molecular dynamics and MM/PBSA calculations.
First, molecular dynamics calculations were carried out for the most promising ligands (L1-L6) identified from the ZINC15 database in preliminary docking studies. The stability of the protein-ligand complexes was assessed based on the time evolution of the potential energy, RMSD, the radius of gyration, and cluster analysis, while the number of hydrogen bonds formed between the ligand and the protein was used as an additional criterion for specific interactions. The binding free energy was then calculated using the MM/PBSA method, which enabled both the estimation of the total binding free energy and the contributions from individual amino acid residues of the AM2 protein.
The results demonstrated that the investigated ligands formed more stable and energetically favorable complexes compared to the reference drugs amantadine and rimantadine. Furthermore, the analysis of amino acid residue contributions revealed that Val27, Ala30, Ser31, Ile33, Ala34 and His37 represent the key binding sites involved in the stabilization of the antiviral compounds.
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