Structure-Activity Relationships of Influenza a M2 Inhibitors

Abstract

The M2 proton channel of influenza A has become resistant to the traditional antiviral drugs amantadine and rimantadine and is a high-priority target for current rational drug design efforts. Recent studies have revealed the interior of the wild-type channel as the primary binding site for amantadine and related antiviral compounds. We have extracted from the literature a set of 291 amantadine-like compounds with experimentally determined antiviral activity. Generating stereoisomers and alternate protonation states for each of these compounds gave a dataset of nearly 1,000 unique structures for in silico analysis. The binding energy and conformation of each structure were predicted using the AutoDock Vina molecular docking program with a recently determined structure of the wild-type channel. In addition, each structure was characterized by additional features, including molecular weight, charge, surface area, volume, and individual components of the Vina scoring function. Comparisons of these calculated values to the experimentally determined activity of each compound will inform future studies seeking to develop new M2 inhibitors.