Ligands docking to ORF8 by co-evolution. Could they reduce the inflammation levels induced by SARS-COV-2 infections?

Abstract

The unique ORF8 is an asymmetric homodimer accessory protein of SARS-COV-2 implicated in pathogenesis by activating excesive human inflammation causing numerous deaths. There is no approved drug targeting ORF8, nor it is known whether any anti-ORF8 drugs could reduce coronavirus-induced excesive inflammation. Computationally combining ligand co-evolution of parent molecules with affinity-ranking by consensus docking, children candidates for ORF8 cavities and ligands were generated. Targeting the interface cavity with the highest affinity children scaffolds, hundreds of grandchildren were generated by specificity-toxicity controlled additional co-evolutions to predict nanoMolar affinities, unique scaffolds, high specificities and low toxicity risks. Although remaining hypothetical without experimental confirmation, these constitute a new methodological attempt to search for drug-like candidates to interfere with SARS-COV-2-dependent excessive inflammation.

Low-toxicity nanoMolar scaffolds with hundreds of variants generated by computational co-evolution into prokaryotic potassium channel cavities

“…Additionally, large numbers of candidates could be used to extract those computationally recognizing known mutations, molecular target variations, and/or off-targets, etc. Something similar was employed with other protein /ligand pair examples for instance to select anticoagulants affecting both rats and their resistant mutants but not humans 46 or monkeypox Tecovirimat-resistant variants 32 .…”

“…The non-toxic fitted-children were DW saved as special 3D *.sdf files using previously described options including mmff94s + minimization 37 . Such saving methods were critically required to preserve their 2D geometries 32 for PyMol visualization (split_states PyMol command) 34 and/or for optimal ADV re-docking.…”

“…Generation rather than screening, were employed in this work to search for new anti-KcsA ligand candidates using the DataWarrior Build Evolutionary Library (DW-BEL) algorithms [2][3][4][5] . Starting from defined parent molecules and their preliminarily identified docking cavity, DW-BEL co-evolution generated tens of thousands raw children and thousands of highly specific cavityfitting children molecules [2][3][4][5]32 selected by their docking affinities. Despite the particular toxicity and/or steric difficulties found when targeting the known KcsA central cavity and/or lipid surfaces, respectively, the random generation of children molecules was very successful.…”

Tailoring evolved-ligands to Plasmodium circumsporozoite-protein

“…Non-toxic nanoMolar affinities drug-like candidates 8 , have been predicted into different protein / ligand pair cavities. To briefly mention, new antibiotics fitting FtsZ of resistant Staphilococcus 9 , alternative Abaucin-derivatives against Acinetobacter lipoprotein 10 , anticoagulant non-human brodifacoum-derived raticide ligands 11 , anti-monkeypox conformers to Tecovirimat-resistance mutants 12 , anti-glycoprotein trimer inner-cavity of omicron coronavirus 13 , antiinflammatory coronavirus-coded protein 14 , new docking to prokaryotic models for human potassium channels 15 , or anti-fish rhabdovirus cross-docking their glycoprotein trimers 16 .…”