Results showed only two possible docking cavities on ORF8, one into the hypervariable loop in the A chain and the other in the dimer AB chain interface. Co-evolution into the AB interface cavity showed that: i) the affinities predicted by a first round of co-evolutions were relatively low, at the 8-9 Kcal/mol (1400-250 nM) ranges (similar to those predicted by previously reported hypothetical disulphide disruptors ) and ii) the numbers of grandchildren that could be generated from top-children (16153 or 46808), were more in the hundreds rather than in the thousand ranges, as usually expected . Thus, DW-BEL co-evolutions using other protein-ligand pairs in our hands usually generated thousands of fitted-children distributed in different scaffolds . In contrast, targeting the ORF8 interface generated hundreds of fitted-grandchildren within unique or few scaffolds while demanding much higher computer memories than in other examples. The strong steric constrains of the highly interdigitated ORF8 interface may explain the evolutionary docking difficulties experienced. Despite those difficulties, hundreds of unique fitted-grandchildren with few scaffold variations predicted docking to their initial docking interface cavity. It was also notice that in contrast to previous work , no ligand molecules were predicted around the disulphide link, even after the widest ADV blind-docking, most probably due to higher steric constrains.