Recent progress in the glycodrug area

Abstract

A new molecular modelling tool for analysing the pre-organization of sialyl Lewisx mimics for binding to E-selectin has been developed. The pre-organization is quantified as the probability for being in the bioactive window of torsional space. The probability data can be correlated with bioactivity, since carbohydrate mimics which populate the bioactive window are likely to be active towards E-selectin, whereas compounds which do not populate the bioactive window are generally inactive. Work is in progress with the aim to further refine this model and to develop quantitative structure activity relationships using the probability data as descriptors. The computational tool has guided our search for new and more active E-selectin antagonists. One of our most active carbohydrate mimics, the cyclohexyl derivative S-5, combines an over ten-fold higher affinity towards E-selectin with a considerably lower molecular weight and a lower hydrophilicity compared to sialyl Lewisx.