Molecular modeling analysis of the interaction of novel bis-cationic ligands with the lipid A moiety of lipopolysaccharide

Lipopolysaccharides (LPS), otherwise termed 'endotoxins', are outer-membrane constituents of Gram-negative bacteria and play a key role in the pathogenesis of 'septic shock', a major cause of mortality in the critically ill patient. We have shown that the pharmacophore necessary for optimal recognition and neutralization of LPS by small molecules requires an interaction between two protonatable positive charges separated by a distance of ∼14 Å, which corresponds to the distance between two anionic phosphates on the glycolipid component of LPS called lipid A. The in silico binding of a diverse set of compounds with bis-amino, -amidino, -guanidino, and -aminoguanidino functionalities, identified as potential lead scaffolds in a high-throughput screen, with lipid A was explored using molecular docking simulations. A weighted expression for binding affinity was trained relative to experimental ED₅₀ measurements, attaining a correlation of R² = 0.66. Our docking results showed that the electrostatic interaction between ligands and lipid A phosphates dominates the expression and varies little across the series, and other ligand-receptor interactions seem to play a secondary role in governing the observed variations in the relative ligand binding affinity. Further, it appears that the ligand internal energy plays the primary role in differentiating between compound binding affinities which also correlated well with experimental ED₅₀ data (R = 0.77). Application of this strategy would be useful in the de novo design of highly active endotoxin-sequestering agents.