It appears that hydroxymethyl moieties are involved in this relaxation.
Molecular docking studies revealed that all three binding moieties are involved in the non-covalent interactions with ChEs for all of the four compounds, albeit not always in the complete accordance with the proposed hypothesis.
Interestingly, the carboxyl moieties in these complexes are noncoordinated, and the pyridyl moieties are either coordinated or noncoordinated, and the noncoordinated carboxyl and pyridyl moieties are involved in intermolecular hydrogen bonds, which are favorable for forming the hydrogen-bonded networks.
The packing analyses revealed that the complex cations are arranged in such a way that N H groups of biimidazole moiety are involved in N H⋯Cl interaction with chloride ion while C H groups of phen/H2biim are involved in C H⋯F interaction with hexafluorophosphate to keep these groups in close proximity.
It is not known how this hydroxyl moiety is involved, but it may make stabilizing H-bonds with the backbone of PA residue A341 and/or the side-chain of PA residue R659 in the PA prepore-receptor complex (Fig. 4A).
Furthermore, deleterious side reactions, such as retro-aldol reactions, can predominate when a ketone moiety is involved.
The uracil moiety is involved in a total of three hydrogen bonds with the protein, with the backbone of Leu442/Pro443 and the His444 side chain (Fig. 2a).
In all these compounds, the 4,6-dimethylpyrimidine moiety extends into the hydrophilic region, similar to what was predicted for compound 35 (Fig. 2b), whereas the para-substituted phenyl moiety is involved in hydrophobic interactions with the far end of the H1 binding pocket.
Interestingly, the ligand has taken an opposite binding pose compared to epibatidine; its aromatic moiety is involved in hydrophobic contacts with the residues of the aromatic cavity within the binding pocket (W53, Y91, W145, Y184, Y191) and the basic bicyclic moiety takes a similar position as the chloropyridinyl ring of epibatidine.
For example, the arginine moiety is involved in high-affinity binding with the sulfonate groups of sulfated glycans (e.g., glycosaminoglycans) as well as with carboxylate groups of hyaluronan and sialic acid through salt-bridge interactions, regulating the function of protein glycan interface.
This feature, combined with tryptophan-fluorescence quenching during loading of a dodecameric lipopeptide antigen, provides a compelling model by which both the lipid and peptide moieties of the lipopeptide are involved in CD1c presentation of lipopeptides.
