Despite missing some loops on the surface, the cryo-EM structure had a sufficiently high resolution and structural integrity inside the tunnel for virtual screening with CaverDock. Because the goal was to block large conformational changes of the s-glycoprotein trimer, we ranked the best binding drugs based on both their overall binding energies and the extent of their contacts with all three monomeric units. Three distinct clusters of drugs with binding profiles showing clear energy minima were identified, each binding to a different region of the tunnel (Figure ). The first cluster consisted of drugs binding in the region immediately behind the first bottleneck of the subunit S1 gorge, between 12 Å and 21 Å from the trimer's surface. Since this region is immediately behind the tunnel's second tightest bottleneck, we hypothesise that drugs in this cluster are flexible enough to cross that narrow part of the tunnel and then undergo a conformational change to adopt an optimal binding conformation.