RESUMEN
Investigation of ligand-protein interactions by the saturation transfer difference (STD) experiment has been well established in the drug discovery process through numerous examples. Thus, binding epitopes may be mapped by comparing signals of the ligand with and without saturation of the protein. Herein, it is shown that a less selective process allows more protons to assist in the saturation of the protein, thereby considerably enhancing the sensitivity of the STD experiment. Increasing the saturation power entails a greater risk of perturbing the ligand; however, an amplitude modulation of the waveform assists this procedure by distributing the applied energy in sidebands.
Asunto(s)
Glicoproteínas/química , Espectroscopía de Resonancia Magnética/métodos , Conformación de Carbohidratos , Selectina E/química , Epítopos , Humanos , Ligandos , Espectroscopía de Resonancia Magnética/estadística & datos numéricos , Glicoproteína Asociada a Mielina/química , Albúmina Sérica/químicaRESUMEN
The trisaccharide substructure 13 of the ganglioside GQ1balpha shows a remarkable affinity for the myelin-associated glycoprotein (MAG). In the search for structurally simplified and pharmacokinetically improved mimics of 13, sialosides with modifications at the reducing and non-reducing end were synthesized. The biological evaluation of mimics 12a-o was performed in a competitive target-based assay. It was found that the relative inhibitory potency (rIP) of antagonist 12h was enhanced by more than 1000-fold in comparison to the reference trisaccharide 13, despite the former having a much simpler structure. In addition, the sialic acid derivatives, for example, 12h, have clearly improved pharmacokinetic properties due to the presence of aromatic moieties, a lower molecular weight, and a reduced number of polar hydroxy functions compared to the reference compound 13.
