article · Scientific Reports
Influenza viruses continue to threaten global public health through seasonal epidemics and potential pandemics. Viral replication depends heavily on polymerase basic protein 2, specifically its cap-binding domain, which serves as an important target for antiviral intervention. Using computational screening methods, potential inhibitors from a diverse chemical library were evaluated through molecular docking and 500-nanosecond molecular dynamics simulations. Among the candidates screened, three molecules, designated compound 1, compound 3, and compound 4, demonstrated promising binding affinities. Compound 4 exhibited the strongest binding affinity, highest structural stability, and the most favourable free energy profile when assessed against a control compound. Compound 1 maintained consistent interactions throughout simulations, whilst compound 3 displayed moderate stability. These findings indicate that compound 4 represents a strong candidate for further development into targeted antiviral agents against influenza.
Influenza causes severe global illness and recurring outbreaks, driving a continuous need for novel therapeutic options. Pinpointing molecules that disrupt critical viral replication machinery, such as the polymerase basic protein 2 cap-binding site, provides an essential starting point for designing effective antiviral treatments to manage seasonal epidemics and pandemic threats.
This research is at an early computational stage. The identified compounds, notably compound 4, offer starting chemical structures for preclinical drug discovery programmes. Potential users include pharmaceutical companies and academic drug discovery units developing influenza therapeutics. Real-world application remains distant, requiring laboratory synthesis, in vitro and in vivo validation, pharmacokinetics evaluation, and resistance profiling.
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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.
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DOI: 10.1038/s41598-024-69816-3
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