The present work explored the co-evolution of ORF8 / ligand pair starting from an artificial pseudoligand parent, because of the affinity limitations of the previously proposed computationally defined ligands . Trial and error attempts resulted in the manual design of a polyCarbon pseudoligand centered at the ORF8 molecule widely extending in 4 directions. The pesudoligand was drawn and manually docked in PyMol to be used as initial parent to start coevolutions (more details in methods). The DataWarrior Build Evolutionary Library (DW-BEL) algorithms were employed here to successfully generate pseudoligand-derived children fitting the ORF8 interface cavities. The best affinity children-scaffolds targeting the interface cavities were then selected for further co-evolutionary refinement, seeking to increase their children affinities and/or additional cavities. DW-BEL co-evolutionary dockings of those new children scaffolds as parents were capable of generating large numbers of highly specific grandchildren. The high computer memories required to perform such coevolutionary searches was higher than in our previously reported work indicating that targeting the ORF8 interface cavities had enormous steric difficulties, most probably due to the interdigitating amino acids between its monomer faces. The generation of children molecules during co-evolution were controlled for molecular weight, hydrophobicity and toxicity risks to avoid unspecificities and/or toxic molecules . The most accurate AutoDockVina (ADV) program quantitatively estimated their affinities, and explore for further docking cavity possibilities in the whole homodimer .