Investigation of Binding Affinity between Potential Antiviral Agents and PB2 Protein of Influenza A: Non-equilibrium Molecular Dynamics Simulation Approach

Abstract

The PB2 protein of the influenza virus RNA polymerase is a major virulence determinant of influenza viruses. It binds to the cap structure at the 5' end of host mRNA to generate short capped RNA fragments that are used as primers for viral transcription named cap-snatching. A large number of the compounds were shown to bind the minimal cap-binding domain of PB2 to inhibit the cap-snatching machinery. However, their binding in the context of an extended form of the PB2 protein has remained elusive. A previous study reported some promising compounds including azaindole and hydroxymethyl azaindole, which were analyzed here to predict binding affinity to PB2 protein using the steered molecular dynamics (SMD) and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) methods. The results show that the rupture force (Fmax) value of three complexes is in agreement with the binding free energy value (ΔGbind) estimated by the MM-PBSA method, whereas for the non-equilibrium pulling work (Wpull) value a small difference between A_PB2-4 and A_PB2-12 was observed. The binding affinity results indicate the A_PB2-12 complex is more favorable than the A_PB2-4 and A_PB2-16 complexes, which means the inhibitor (12) has the potential to be further developed as anti-influenza agents in the treatment of influenza A.

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Recent Developments in Free Energy Calculations for Drug Discovery

“…Influenza viral infection causes respiratory illnesses commonly called the flu that can lead to death. Work on antivirals to treat influenza includes utilizing amantadine probes to block influenza M2 proton channels to prevent virus replication ( Tzitzoglaki et al, 2020 ), analyzing the effects of the hemagglutinin mutations on binding affinity to human receptors ( Zhou et al, 2018 ), screening inhibitors for the PB2 protein of influenza RNA polymerase to inhibit generation of RNA primers essential for replication ( Pham et al, 2020 ), optimizing neuraminidase inhibitors as lead compounds ( Yu et al, 2019 ), and characterizing potential influenza polymerase inhibitors ( Pérez-Sánchez et al, 2021 ). Ebola causes hemorrhagic fever and molecular interactions between the monoclonal antibody ADI-15946 and the Ebola GPcl receptor is studied ( Hou and Zhang, 2020 ).…”