This computational co-evolutionary work explored new ligand alternatives to Tecovirimat (ST-246 or TPOXX) maintaining docking to the Tecovirimat-resistant mutants that arised during the 2022 MPOX global outbreak of MonkeyPox Virus (MPXV) clade II and still to be identified in the 2024 clade I global outbreak. The Tecovirimat reference FDA-approved inhibitor for vaccinia poxvirus , was used here as the parent molecule to derive co-evolution children. Randomly generated children were selected by best fitting F13L alphafold modeled blind-docking identified cavities, including those from pooled mutations associated with Tecovirimat-resistance. Co-evolutions employed the DataWarrior Build Evolutionary Library (DWBEL) algorithms . Briefly, DWBEL mimicked natural co-evolution by randomly generating tens of thousands of Tecovirimatderived children, discarding those low fitting and saving the best F13L-fitted children , rather than screening preexisting large compound libraries. By incorporating Toxicity Risk assessment and increasing computer memories during co-evolution, thousands of non-toxic children were generated that predicted drug-like properties, nanoMolar affinities, and higher specificities while conserving their initially targeted F13L mutant docking cavities.