Design, synthesis and biological evaluation of novel zanamivir derivatives as potent neuraminidase inhibitors.

Neuraminidase (NA) is an important antiviral drug target. Zanamivir is one of the most potent NA inhibitors. In this paper, a series of zanamivir derivatives as potential NA inhibitors were studied by combination of molecular modeling techniques including 3D-QSAR, molecular docking, and molecular dynamics (MD) simulation. The results show that the best CoMFA (comparative molecular field analysis) model has q2 = 0.728 and r2 = 0.988, and the best CoMSIA (comparative molecular similarity indices analysis) model has q2 = 0.750 and r2 = 0.981, respectively. The built 3D-QSAR models show significant statistical quality and excellent predictive ability. Seven new NA inhibitors were designed and predicted. 20 ns of MD simulations were carried out and their binding free energies were calculated. Two designed compounds were selected to be synthesized and biologically evaluated by NA inhibition and virus inhibition assays. One compound (IC50 = 0.670 µM, SI > 149) exhibits excellent antiviral activity against A/WSN/33 H1N1, which is superior to the reference drug zanamivir (IC50 = 0.873 µM, SI > 115). The theoretical and experimental results may provide reference for development of new anti-influenza drugs.