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

Abstract

Human potassium channels (Kir) are implicated in numerous dysfunction diseases genetically affecting cardiovascular, skeletal-muscle and/or synaptic-neuronal functions. Variations in Kir sequences, organ distribution differences and toxicity of some of their known inhibitors, require alternative drugs to interfere specifically with each human Kir molecular species. In this work, a prokaryotic asymmetric transmembrane homotetramer potassium (K+) channel protein highly homologous to Kirs has been used as their model. Computational methods combining molecular parent co-evolutions confirmed by consensus docking, were explored as possible prove-of-concept to generate rather than screen for numerous KcsA docking-ligands. The explorations of the KcsA central cavity and of their interface lipid-binding shallow-grooves, predicted highly specific novel scaffolds with low-toxicity risks, displaying hundreds of molecular variations of new scaffolds within nanoMolar-ranged affinities. Experimental validation and/or additional computational research on human Kirs could be attempted in the future.

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 .…”

“…Therefore, DWBEL selected the non-toxic best-fitted children conformers as output. To prepare for ADV docking, the non-toxic fitted-children were further filtered with a macro designed to exclude any survivor molecules with remaining preferences for mutagenesis, tumorigenicity, reproductive interference, irritant molecular signatures, and/or nasty functions by screening the presence of hundreds of those motifs 12,15,16,50 . The non-toxic fitted-and filtered children were ordered from low to high DWBEL docking-scores (high to low affinities, NN numbers) and finally saved as *.sdf 3D files.…”