Overlay of crystal structures and models of 1 and 16 bound to RT. Co-crystal structures of WT RT bound to 1 (gray) and 16 (green) show only minimal differences in the position of the compound and the conformation of the binding pocket. This is consistent with the similar activity of the two compounds against WT RT (0.2nM for 1 and 0.4nM for 16). Models were generated for each compound bound to Y188L RT (1: magenta, 16:cyan). Both models show the compound positioned approximately one angstrom further into the binding pocket than in the respective WT co-crystal structure. This results in a repositioning of the F227 and W229 side chains and a shift in the overall positioning of the β12-β13 hairpin (shown as a ribbon). These differences in the modeled interactions are consistent with the observed difference in antiviral activities against vectors using Y188L RT (2.3nM for 1 and 29nM for 16).