Targeting the A3A monomer ssDNA-binding site The star8 parent and its A3A ADV-docked cavity employed as inputs for DWBEL co-evolutions, randomly generated 64145 raw-children, of which 4411 were selected as non-toxic fitted-children. Among the children derivatives, the NN1517 child-lead predicted 414 nM ADV affinity. However, although such affinity was higher than star8, higher affinities were desirable to reduce both any crossdocking with other human A3 enzymes and possible side-effects if applied in vivo. Therefore, higher affinities (lower docking scores) were searched by consecutively performing DWBEL / ADV iterations using their corresponding leadchildren as parents. After 4 iterative co-evolutions, top-children predicting ~ 6 nM ADV affinities were generated (Table ). The rank profiles of the corresponding non-toxic fitted-children confirmed the increasing affinities with the number of iterations (Figure , cyan, green, orange, red circles). To study possible cross-dockings to the other A3 human enzymes, their amino acid sequences and 3D structures were aligned. The 2D alignment predicted 4 conserved Cysteins (Figure ) and amino acids around their hypothetical ssDNA-binding cavities (Figure , XXX). The 3D alignment predicted that their 3D structures differed only < 0.8 Å, except A3H which differed 1.3 Å. Therefore, gridboxes of 20x20x20 Å centered to their unique centerofmass after 3D alignment, and including their dC mutational target were selected for ADV docking for each of the A3 enzymes: A3A, A3B,A3C,A3D, A3F,A3G,A3H and AID (Figure , grey gridbox) (Supplementary Materials / A3monomers-3Daligned.pse). Finally, 411 A3A top-children predicting affinities ~ < 90 nM, were selected from the fourth iteration to compare affinities through all A3 enzymes (Figure