In silico discovery of novel fructose scavengers for the treatment of fructose malabsorption

Fructose malabsorption is the inability to absorb fructose through the small intestines, and the subsequent build-up of fructose concentration in the intestinal lumen, with symptoms related to that of Irritable Bowel Syndrome. The sequestering and subsequent elimination of excess fructose from the intestinal lumen provides a novel approach to the treatment of fructose malabsorption. Phenylboronic acids possess the ability to reversibly bind to 1,2-cis-diols, such as those found in monosaccharides, and subsequent modifications to phenylboronic acids can result in sugar binding at physiological pH. However, the design of fructose scavengers requires the development of an oral drug that is not absorbed through the small intestines itself. Much research has gone into the identification of physiological descriptors that indicate oral bioavailability; however, research into the identification of small, non-systemic compounds is much more limited. This research is two-fold. The first step was to develop a novel, quantitative metric for scoring compounds based on their likelihood for non-systemic activity and applying that metric to a large dataset of literature and patent-based compounds containing aryl-boronic acid moieties. From this analysis, a longlist of compounds was processed using high-throughput, computational calculations in order to predict fructose affinity. Selected compounds were then modified in order to further optimise the compounds. Finally, combining the results of novel ‘anti-druglikeness’ with the fructose binding predictions, as well as a subjective analysis of synthetic feasibility, allowed for the ranking of shortlisted compounds in order of the best fit for the defined criteria.