The conformational analysis and proton transfer of neuraminidase inhibitors: a theoretical study.

With the aid of density functional calculations, it was revealed that neuraminidase (NA) inhibitors (Scheme 1) exist exclusively in the neutral form. However, the docking and molecular dynamics simulations indicated that the zwitterionic, rather than neutral, isomers are the active form in NA-receptors. The neutral and zwitterionic isomers of BA (Compound 7 in Scheme 1) are quite different in structure and is therefore expected to show distinct bioactivities. With the addition of four water molecules, the geometry of the neutral isomer (nBA4) is induced to resemble the zwitterion and remains rather stable throughout the proton transfer process (nBA4 --> zBA4); in addition, the energy difference between the zwitterionic vs. the neutral isomer is lowered from 24.76 to 2.54 kcal mol(-1). The zwitterion is the predominant isomer in aqueous solution, consistent with the conformational preference in NA-receptors. The proton transfer process of nBA4 --> zBA4 is divided into two elementary steps. Step 1, rather than step 2, plays a decisive role, owing to the larger energy barrier; however, step 1 is not assisted by solvent water, even if it is not water-suppressed. Accordingly, the proton transfer process that leads to the formation of zwitterions is not facilitated in aqueous solution, albeit they may be more stable than the neutral isomers. It is thus suggested that the designed antiviral inhibitors should be facile to transform into the zwitterionic form in aqueous solution. In this way, the oral bioavailability of the antiviral drugs can be improved.