Int J Med Sci 2020; 17(13):2031-2039. doi:10.7150/ijms.46231

Research Paper

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

Tri Pham1,2, Hoang Linh Nguyen1,2, Tuyn Phan-Toai1, Hung Nguyen1✉

1. Institute for Computational Science and Technology, Ho Chi Minh City, Vietnam.
2. VNUHCM-University of Technology, Ho Chi Minh City, Vietnam.

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Citation:
Pham T, Nguyen HL, Phan-Toai T, Nguyen H. Investigation of Binding Affinity between Potential Antiviral Agents and PB2 Protein of Influenza A: Non-equilibrium Molecular Dynamics Simulation Approach. Int J Med Sci 2020; 17(13):2031-2039. doi:10.7150/ijms.46231. Available from http://www.medsci.org/v17p2031.htm

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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.

Keywords: Azaindole (4 and 16), hydroxymethyl azaindole (12), protein_PB2, SMD, MM-PBSA