To define the general trends of the children generated by targeting each of the A3 ssDNA-docking sites, their rank profiles were compared. The A3A rank profiles predicted ~10-100-fold higher affinities than those from A3B, A3D, A3C, A3F,A3G, A3H and AID (Figure ). Top-children NN216, NN735 and NN1219 predicting ~ <10 nM affinities to A3A were selected to further comparisons among A3-specific affinities and molecular structures (Figure ). The A3A ~10-100-fold higher affinities of the top-children to A3A compared to the affinities predicted for the same top-children docking to A3B, A3D, A3C, A3F,A3G, A3H and AID, confirmed the rank profile approximations (Figure , bar graphic). The topchildren molecular structures were very similar. Thus, the top-children predicted molecules containing star-shaped 3-arm molecules with central pyrazolidines (5atom rings with two Nitrogens), provided with two-arms containing 1 or 2 bencenes and one arm with more variable atoms and a terminal piperidine ring linked to either benzene or pyridine rings (Figure , red encircled atoms). Targeting the A3A dimer-interface The star36 parent and its corresponding ADV docked interface-cavity defined one A3A docking-interface located at the bottom of the dimer predicting the highest affinity (Table1 and GraphycalAbstract, green spheres). The star36 parent and cavity were uploaded to DWBEL for co-evolutionary docking. DWBEL randomly generated 36601 raw-children of which 2776 were selected as nontoxic and fitted-children. Their lead child predicted 12 nM ADV affinity (Table ). As mentioned above, co-evolution iterations were then performed to explore for any affinity improvements. In this case, only one more iterative co-evolution predicted ~ 6 nM affinity top-child which was high enough to reduce any crossdocking with the other human A3 enzymes and possible side-effects if applied in vivo. The rank profiles confirmed the increasing top-children affinities with the number of iterations (Figure , orange, red triangles). To study possible 3D cross-dockings to the A 35 ,B 36 ,C 24 ,F 37 ,G 25 , H 38 ,AID 26 A3 ABdimer-interface models were obtained from their pdb files or modeled by alphafold (A3D) or by monomer-to-monomer alignment (A3B). The 3D alignment of the resulting A3 dimer models predicted differences between 2 to 20 Å (Figure ), mostly due to their disordered amino acid contents and relative positions of their AB monomers in the heterodimer structures. Nevertheless, the 3D-alignments predicted some consensus dimer interfaces. Therefore, one 20x20x20 Å gridbox centered at the similar centerofmass after A3 alignment, included most of their corresponding A3A dimer-interfaces (Figure , white lines grey gridbox). Such gridboxes were employed to ADV-dockings of A3A, A3B,A3C,A3D, A3F,A3G,A3H and AID dimers (Supplementary Materials / A3dimer-3DAligned.pse). Finally, 430 top-children (affinities ~ < 90 nM), were selected from the second iteration to compare affinities through the A3 enzymes (Figure