Exploitation of the Catalytic Site and 150 Cavity for Design of Influenza A Neuraminidase Inhibitors
2013
Adabala, Pal John Pal | LeGresley, Eric B. | Bance, Nicole | Niikura, Masahiro | Pinto, B Mario
We report here the exploitation of the 150 cavity in the active site of influenza A viral neuraminidases for the design of novel C-6 triazole-containing Tamiflu derivatives. A general and convenient synthetic route was developed by utilizing a highly substituted cyclic Baylis–Hillman acetate as an active precursor for azide substitution via suprafacial allylic azide [3,3]-sigmatropic rearrangement. Virus replication inhibitory assays in vitro of these triazole derivatives containing either an amino or guanidino function indicated that the guanidinium compound showed the higher efficacy against a strain with N2 subtype at a concentration of 2 × 10–⁵ M but did not inhibit replication of a strain with N1 subtype even at a concentration of 10–⁴ M. In order to probe the nature of the enzyme–inhibitor interactions, molecular dynamics simulations were performed on complexes of these compounds with different neuraminidase enzymes. The results indicated that the candidate inhibitors occupy both the 150 cavity and catalytic site but with alternating occupancy.
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