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

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.