Green Drug Discovery: Novel Fragment Space from the Biomass-Derived Molecule Dihydrolevoglucosenone (Cyrene™)

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 (Cyrene (TM)), 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.

Automated summary

Biomass-derived molecules have the potential for sustainable drug discovery, but their exploration is hindered by the dominance of old-fashioned screening compounds in classical high-throughput screening libraries. We propose a fragment-based drug discovery approach as an efficient method to navigate biomass-derived drug space. In a proof-of-concept study using dihydrolevoglucosenone (Cyrene TM), we generated a diverse fragment library with good physicochemical properties and potential for novel drug candidates based on renewable resources.