Computed relative binding energies (ΔGbinding) showed that remdesivir presented the strongest binding (precision range -8.7 to -8.5 kcal/mol), followed by dATP ( -8.6 to -8.4 kcal/mol) and tenofovir ( -7.7 to -7.5 kcal/mol). The three ligands shared the same binding site and were forced to adopt a different conformation in order to allow the insertion of the incoming nucleotide into the nascent RNA. Docking structures of dATP, remdesivir, and tenofovir ensembles are displayed in Figure 1. Including the RNA chains/magnesium ions in the analysis reduced the computed ΔGbinding for all three ligands while maintaining a similar affinity gradient (see supplementary material, S2). We further observed that the lowest binding energy conformations did not always show the expected interactions between the template-nascent RNA strands and the analyzed ligand. Thus, we searched for the poses with maximum interaction with the template RNA strand and computed the ΔGbinding. In the case of ATP and remdesivir, we found that those poses remain close to the lowest computed ΔGbinding (ca. 0.1 kcal/mol), while the tenofovir ensemble showed a greater difference between the pose with RNA interactions and the lowest ΔGbinding poses (ca. 0.5 kcal/mol). The most probable driver for the lower ΔGbinding of remdesivir compared to ATP is the extra H-bond between the cyano group and the U927 nucleotide of the nascent RNA strand, which is lacking within the tenofovir structure.