Identifying inhibitors of -haematin formation with activity against chloroquine-resistant Plasmodium falciparum malaria parasites via virtual screening approaches

The biomineral haemozoin, or its synthetic analogue beta-haematin (beta H), has been the focus of several target-based screens for activity against Plasmodium falciparum parasites. Together with the known beta H crystal structure, the availability of this screening data makes the target amenable to both structure-based and ligand-based virtual screening. In this study, molecular docking and machine learning techniques, including Bayesian and support vector machine classifiers, were used in sequence to screen the in silico ChemDiv 300k Representative Compounds library for inhibitors of beta H with retained activity against P. falciparum. We commercially obtained and tested a prioritised set of inhibitors and identified the coumarin and iminodipyridinopyrimidine chemotypes as potent in vitro inhibitors of beta H and whole cell parasite growth.