Structural and biochemical studies elucidate that PAN may contribute to the host protein shutdown observed during influenza A infection. Thus, inhibition of the endonuclease activity of viral RdRP is an attractive approach for novel antiviral therapy. In order to envisage structurally diverse novel compounds with better efficacy as PAN endonuclease inhibitors, a ligand-based-pharmacophore model was developed using 3D-QSAR pharmacophore generation (HypoGen algorithm) methodology in Discovery Studio. As the training set, 25 compounds were taken to generate a significant pharmacophore model. The selected pharmacophore Hypo1 was further validated by 12 compounds in the test set and was used as a query model for further screening of 1916 compounds containing 71 HIV-1 integrase inhibitors, 37 antibacterial inhibitors, 131 antiviral inhibitors and other 1677 approved drugs by the FDA. Then, six compounds (Hit01–Hit06) with estimated activity values less than 10 μM were subjected to ADMET study and toxicity assessment. Only one potential inhibitory ‘hit’ molecule (Hit01, raltegravir’s derivative) was further scrutinized by molecular docking analysis on the active site of PAN endonuclease (PDB ID: 6E6W). Hit01 was utilized for designing novel potential PAN endonuclease inhibitors through lead optimization, and then compounds were screened by pharmacophore Hypo1 and docking studies. Six raltegravir’s derivatives with significant estimated activity values and docking scores were obtained. Further, these results certainly do not confirm or indicate the seven compounds (Hit01, Hit07, Hit08, Hit09, Hit10, Hit11 and Hit12) have antiviral activity, and extensive wet-laboratory experimentation is needed to transmute these compounds into clinical drugs.

Background: Viral resistance to existing inhibitors and the time-dependent effectiveness of neuraminidase inhibitors have limited the number of antivirals that can be used for prophylaxis and therapeutic treatment of severe influenza infection. Thus, there is an urgent need to develop new drugs to prevent and treat influenza infection. Objective: The aim of this study was to design and synthesize a novel series of 2-ureidonicotinamide derivatives, and evaluate their anti-IAV activities. Furthermore, we predicted the abilities of these compounds inhibiting PA-PB1 subunit and forecasted the docking poses of these compounds with RNA polymerase protein (PDB ID 3CM8). Method: The novel designed compounds were synthesized using classical methods of organic chemistry and tested in vitro for their abilities inhibiting RNP and against influenza A virus. In addition, the 23 synthesized molecules were subjected to the generated pharmacophore Hypo1 to forecast the activity target PA-PB1 subunit of RNA polymerase. The ADMET pharmacokinetic parameters were calculated by the ADMET modules in Discovery Studio 2016. The docking results helped us to demonstrate the possible interactions between these compounds with 3CM8. Results: The synthesized 2-ureidonicotinamide derivatives were characterized as potent anti-influenza inhibitors. The target compounds 7b and 7c demonstrated significant antiviral activities, and could be considered as novel lead compounds of antiviral inhibitors. In addition, compound 7b revealed suitable ADME properties expressed, and might be a significant RNA polymerase inhibitor targeting PA-PB1 subunit based on the predictable results and the docking results. Conclusion: This study revealed a novel series of compounds that might be useful in the search for an effective drug against influenza virus.