The consensus top-children predictions proposed here are limited in their possible drug-like applications because: i) the small number of available mutations characterized from Tecovirimat-resistant patients, ii) the mutant strategy of pooling the most abundant mutations, rather than targeting one-by-one each individual mutations, and iii) the absence of F13L crystallographically solved models. Apart from all those mentioned above, other limitations arised, for instance, because the fixed rather than dynamic docking-cavities employed, the absence of water interactions, or the always incomplete exploration of the vast chemotype/chemical space alternatives . Additionally, most probably other docking cavities still remain to be further explored, such as those that may be appearing at the interfaces of F13L with other interacting proteins like B6Rpoxvirus, and/or TIP47-host proteins. Nevertheless, the proposed strategy might be valid to raise more ligands for future work when more F13L mutations would be available. The MPXV 2022 global outbreak identifying F13L mutations appearing on Tecovirimat-resistant immuno compromised human patients, suggests that alternative Tecovirimat drugs are required to include those from the most recent 2024 outbreak . Some of these ideas may help to explore alternative ligands by using the most recent DWBELvs6 written in more recent Java (BellSoft Liberica openJDK, ) which allowed for optimal use of computer memories during DWBEL co-evolutions (). Some of the most remarkable results on MPXV F13L mutants were the high speed to generate high numbers of unique nanoMolar affinities fitting the F13L1 and F13L2 mutant model cavities. Many different co-evolution trajectories were identified when providing higher computer memories and more consecutive runs. However, chemical synthesis will be required for confirmatory experimental tests. At this time some recent breakthrough ultrasearch technologies targeting extralarge combinatorial chemical spaces are becoming available from several companies. Among them, Enamine (), Enamine Real Space (), Freedom Space 3.0 (), and ChemSpace (). For instance, the Alipheron Hyperspace, available from the new DW 6.2 version (), offers > ~ 50000 millions of virtual molecules by cheapfast combinatorial chemical synthesis. Some of these novel modular combinatorial synthesis methodologies may allow to experimentally test a high number of computational predictions with lower synthesis costs. H His H Amino acid positions, were those at F13L0, except for the 267 N which was either mutated to D or deleted (▼, Purple row). For comparative purposes, the identification numbers > 267 on the F13L2 267 N deleted mutations were corrected to their "initial" positions in F13L0 and F13L1. *red number, F13L amino acid at vaccinia mutation to both ST246 and IMCBH resistance . *green numbers, F13L mapping of conserved amino acids at the near-canonical phospholipaselike motif in poxviruses and histidines possibly participating in their phospholipase activity. Blue and yellow rectangle backgrounds, residues of F13L1 and F13L2 predicted nearby 4 Å to reference ligand and top-children atoms (LigPlus/LigPlot). Yellow background numbers to the left, F13L amino acids previously identified by Tecovirimat (ST246) docking in the MPXV strain of 2007 ( 353 E) . H, LigPlus/LigPlot predicted Hydrogen bonds.