We obtained a ranking of the best binders from the PCA and selected the top ten for further analysis (Figure ). These ligands had consistently low binding energies in all of the studied protein structures and exhibited a high percentage of contacts with all three monomeric units of the sglycoprotein trimer during the CaverDock simulations. Although drugs in clusters S1, S3, and S5 occasionally formed contacts with only one monomer, these cases represented less than 10% of the corresponding trajectory. This ranking reflects our assumption that strong interactions with all three monomers in different states of the trimer will reduce the trimer's capacity for conformational change, which is essential for the biological activity of the spike glycoprotein. We also found that multivariate statistical methods were needed to rank the drugs meaningfully. For example, a simple ranking of the drugs based on their minimum binding energies would not have placed Daclatasvir (Figure ) in the top 10 because its binding energies for all six conformations are higher than those of some drugs that were not selected. It was thus clear that interaction with all three monomers was weighted strongly in the ranking of the drugs; for three of the studied protein states, Daclatasvir was observed in contact with two and three subunits of the s-glycoprotein trimer, and in the remaining three states (clusters s1, s3 and s5) it was in contact with two or three subunits for at least 96.4% of the trajectory (SI-Table1).