Structural and free energy landscape analysis for the discovery of antiviral compounds targeting the cap-binding domain of influenza polymerase PB2

Amr S Abouzied; Saad Alqarni; Kareem M Younes; Sanad M Alanazi; Dana M Alrsheed; Rawabi K Alhathal; Bader Huwaimel; Akram M Elkashlan

doi:10.1038/s41598-024-69816-3

Structural and free energy landscape analysis for the discovery of antiviral compounds targeting the cap-binding domain of influenza polymerase PB2

Sci Rep. 2024 Oct 25;14(1):25441. doi: 10.1038/s41598-024-69816-3.

Authors

Amr S Abouzied^{1

2}, Saad Alqarni¹, Kareem M Younes^{1

3}, Sanad M Alanazi⁴, Dana M Alrsheed⁴, Rawabi K Alhathal⁴, Bader Huwaimel^{1

5}, Akram M Elkashlan⁶

Affiliations

¹ Department of Pharmaceutical Chemistry, College of Pharmacy, University of Hail, 81442, Hail, Saudi Arabia.
² Department of Pharmaceutical Chemistry, Egyptian Drug Authority, Giza, Egypt.
³ Department of Analytical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
⁴ College of Pharmacy, University of Hail, 81442, Hail, Saudi Arabia.
⁵ Medical and Diagnostic Research Center, University of Ha'il, 55473, Hail, Saudi Arabia.
⁶ Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, El-Sadat, Egypt. akram.elkashlan@fop.usc.edu.eg.

Abstract

Influenza poses a significant threat to global health, with the ability to cause severe epidemics and pandemics. The polymerase basic protein 2 (PB2) of the influenza virus plays a crucial role in the viral replication process, making the CAP-binding domain of PB2 an attractive target for antiviral drug development. This study aimed to identify and evaluate potential inhibitors of the influenza polymerase PB2 CAP-binding domain using computational drug discovery methods. We employed a comprehensive computational approach involving virtual screening, molecular docking, and 500 ns molecular dynamics (MD) simulations. Compounds were selected from the Diverse lib database and assessed for their binding affinity and stability in interaction with the PB2 CAP-binding domain. The study utilized the generalized amber force field (GAFF) for MD simulations to further evaluate the dynamic behaviour and stability of the interactions. Among the screened compounds, compounds 1, 3, and 4 showed promising binding affinities. Compound 4 demonstrated the highest binding stability and the most favourable free energy profile, indicating strong and consistent interaction with the target domain. Compound 3 displayed moderate stability with dynamic conformational changes, while Compound 1 maintained robust interactions throughout the simulations. Comparative analyses of these compounds against a control compound highlighted their potential efficacy. Compound 4 emerged as the most promising inhibitor, with substantial stability and strong binding affinity to the PB2 CAP-binding domain. These findings suggest that compound 4, along with compounds 1 and 3, holds the potential for further development into effective antiviral agents against influenza. Future studies should focus on experimental validation of these compounds and exploration of resistance mechanisms to enhance their therapeutic utility.

Keywords: Free binding energy; Free energy landscape; Influenza virus; Molecular dynamics simulations; PB2 CAP-binding domain; Virtual screening.

MeSH terms

Antiviral Agents* / chemistry
Antiviral Agents* / pharmacology
Binding Sites
Drug Discovery*
Humans
Influenza, Human / drug therapy
Influenza, Human / virology
Molecular Docking Simulation*
Molecular Dynamics Simulation*
Protein Binding
RNA-Dependent RNA Polymerase* / antagonists & inhibitors
RNA-Dependent RNA Polymerase* / chemistry
RNA-Dependent RNA Polymerase* / metabolism
Thermodynamics
Viral Proteins* / antagonists & inhibitors
Viral Proteins* / chemistry
Viral Proteins* / metabolism

Substances

Antiviral Agents
Viral Proteins
RNA-Dependent RNA Polymerase
PB2 protein, influenza virus
PB2 protein, Influenzavirus A

Grants and funding

RG-23 204/University of Hail