A novel inhibitor against the bromodomain PfBDP1 of the malaria pathogen Plasmodium falciparum

The rise of drug resistances in malaria necessitates the exploration of novel therapeutic strategies. Targeting epigenetic pathways could open new, promising treatment avenues. In this study, we focus on PfBDP1, an essential bromodomain protein in P. falciparum. Utilizing the pan-selective bromodomain inhibitor MPM6, we identified a potent initial hit and subsequently developed it into a nanomolar binder. Through a combination of virtual docking, isothermal titration calorimetry, and X-ray crystallography, we elucidated the molecular interactions of the new inhibitors with PfBD1. Our findings include the first cocrystallized structures of PfBD1 and PvBD1 with these inhibitors, providing insights into their binding mechanisms. Further validation using conditional knockdown of PfBDP1 in P. falciparum demonstrated parasite sensitivity to the inhibitor, underscoring its potential as a targeted therapeutic approach against malaria.