Co-evolution ligands to Tecovirimat-resistant F13L mutations of MonkeyPox Virus

Because of the emergence of F13L mutations in MonkeyPox Virus (MPXV)-infected patients with resistances to Tecovirimat-treatment, alternative drugs are actively searched. Aiming to help on these searches, computational strategies to generate rather than screen for new drug-like ligand candidates were explored here. Ligands were predicted by i) thousands of Tecovirimat-derived children generated by co-evolution fitting predicted docking cavities at either F13L1 or F13L2, and ii) docking Tecovirimat-derived top-children to F13L-mutant resistant models isolated from Tecovirimat-treated patients. Top-children-fitting F13L-mutant docking-cavities predicted novel scaffolds, nanoMolar affinities, high specificities, absence of known toxicities and similar conservation of their targeted Tecovirimat-docking cavities. Despite their limitations, similar proved-on-concept strategies might be fine-tuned to computational explore for new drugs docking to most prevalent Tecovirimat-resistance mutations.