Abstract
Drug repurposing can quickly and effectively identify novel drug repurposing opportunities. The PA endonuclease catalytic site has recently become regarded as an attractive target for the screening of anti-influenza drugs. PA N-terminal (PAN) inhibitor can inhibit the entire PA endonuclease activity. In this study, we screened the effectivity of PAN inhibitors from the FDA database through in silico methods and in vitro experiments. PAN and mutant PAN-I38T were chosen as virtual screening targets for overcoming drug resistance. Gel-based PA endonuclease analysis determined that the drug lifitegrast can effectively inhibit PAN and PAN-I38T, when the IC50 is 32.82 ± 1.34 μM and 26.81 ± 1.2 μM, respectively. Molecular docking calculation showed that lifitegrast interacted with the residues around PA or PA-I38 T’s active site, occupying the catalytic site pocket. Both PAN/PAN-I38T and lifitegrast can acquire good equilibrium in 100 ns molecular dynamic simulation. Because of these properties, lifitegrast, which can effectively inhibit PA endonuclease activity, was screened through in silico and in vitro research. This new research will be of significance in developing more effective and selective drugs for anti-influenza therapy.
Highlights
Influenza is an infectious disease that causes 300,000 to 500,000 human deaths globally per year [1,2]
To develop the new Polymerase Acidic (PA) domain (PAN) endonuclease inhibitor structure, we performed the virtual screening protocol based on the PAN and mutant PAN-I38T structure
The method employed in this work could be interacting with PAN or PAN-I38T were sorted by affinity score
Summary
Influenza is an infectious disease that causes 300,000 to 500,000 human deaths globally per year [1,2]. The Influenza virus genome is composed of eight negative RNA segments encoded by multiple viral proteins, including PB2, PB1, PA, HA, NP, NA, M1, and NS1 [3,4]. RNA-dependent RNA polymerase (RdRp) is critical for virus RNA transcription and replication and comprises PA, PB1, and PB2 (Figure 1). The N-terminal of PA domain (PAN ). Contains an endonuclease active pocket and plays a crucial role in influenza virus polymerase activity. Drugs that abolish PAN endonuclease activity or disturb the assembly of. RdRp can effectively inhibit the replication of the influenza virus [5]. The PAN endonuclease domain is highly conserved among different influenza virus subtypes, indicating that
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