A novel small molecule displays two different binding modes during inhibiting H1N1 influenza A virus neuraminidases

Neuraminidase (NA) inhibitors can suppress NA activity to block the release of progeny virions and are effective against influenza viruses. As potential anti-flu drugs with unique functions, NA inhibitors are greatly concerned by the worldwide scientists. It has been reported recently that one of the novel quindoline derivatives named 7a, could inhibit both A/Puerto Rico/8/34 (H1N1) NA (NA_PR) and A/California/04/09 (H1N1) NA (NA_CA). However, potential structure differences in the active site could be easily detected between the NA_PR and NA_CA according to the flexibilities of their 150-loops located catalytic site. And no obvious 150-cavity could be observed in NA_CA crystal structure. In order to explore whether 7a could trigger the inhibition against these two NAs in the same way, a serial molecular dynamics simulation approach were applied in this study. The results indicated that 7a could be adopted under a relatively extended pose in the active center of NA_PR. While in NA_CA-7a complex, the derivate preferred to be recognized and located on the side of active center. Interestingly, the potential of 7a was also found to be able to change the flexibility of the 150-loop in NA_CA that is absent of 150-cavity. Furthermore, a 150-cavity-like architecture could be induced in the active site of NA_CA. The results of this study revealed two kinds of binding modes of this novel small molecule inhibitor against NAs that might provide a theoretical basis for proposing novel inhibition mechanism and developing future influenza A virus inhibitors.