Green Drug Discovery: Novel Fragment Space from the Biomass-Derived Molecule Dihydrolevoglucosenone (CyreneTM)
Tom Dekker, Jaap W. Harteveld, Gábor Wágner, Max C. M. de Vries, Hans Custers, Andrea C. van de Stolpe, Iwan J. P. de Esch, Maikel Wijtmans
Abstract
Biomass-derived molecules can provide a basis for sustainable drug discovery. However, their full exploration is hampered by the dominance of millions of old-fashioned screening compounds in classical high-throughput screening (HTS) libraries frequently utilized. We propose a fragment-based drug discovery (FBDD) approach as an efficient method to navigate biomass-derived drug space. Here, we perform a proof-of-concept study with dihydrolevoglucosenone (CyreneTM), a pyrolysis product of cellulose. Diverse synthetic routes afforded a 100-membered fragment library with a diversity in functional groups appended. The library overall performs well in terms of novelty, physicochemical properties, aqueous solubility, stability, and three-dimensionality. Our study suggests that Cyrene-based fragments are a valuable green addition to the drug discovery toolbox. Our findings can help in paving the way for new hit drug candidates that are based on renewable resources.