Nanomolar anti-sickling compounds identified by ligand-based pharmacophore approach

Adenosine receptors are considered as potential targets for drug development against several diseases. The discovery of subtype 2B adenosine receptors role in erythrocyte sickling process proved its importance to neglected diseases such as sickle cell anemia, which affects approximately 29.000 people around the world, but whose treatment is restricted to just one FDA approved drug (hydroxyurea). In order to widen the therapeutic arsenal available to treat sickle cell anemia patients, it is imperative to identify new lead compounds that modify the sickling course and not just its symptoms. In order to accomplish this goal, ligand-based pharmacophore models that differentiate true ligands from decoys and enlighten the structure-activity relationship of known RA2B antagonists were employed screen the lead-like subset of the ZINC database. Following a chemical diversity analysis, 18 compounds were selected for biological evaluation. Among them, one molecule Z1139491704 (pEC50 = 7.77 ± 0.17) has shown better anti-sickling activity than MRS1754 (pEC50 = 7.63 ± 0.12), a commercial RA2B antagonist. Moreover, these compounds exhibited no cytotoxic effect at low micromolar range on mammalian cells. In conclusion, the sound development of validated ligand-based pharmacophore models proved essential to identify novel chemical scaffolds that might be useful to develop anti-sickling drugs.