QSAR Classification Models for Prediction of Hydroxamate Histone Deacetylase Inhibitor Activity against Malaria Parasites

Malaria, caused by Plasmodium parasites,
results in >400,000 deaths annually. There is no effective vaccine,
and new drugs with novel modes of action are needed because of increasing
parasite resistance to current antimalarials. Histone deacetylases
(HDACs) are epigenetic regulatory enzymes that catalyze post-translational
protein deacetylation and are promising malaria drug targets. Here,
we describe quantitative structure–activity relationship models
to predict the antiplasmodial activity of hydroxamate-based HDAC inhibitors.
The models incorporate P. falciparum in vitro activity data for 385 compounds containing a hydroxamic
acid and were subject to internal and external validation. When used
to screen 22 new hydroxamate-based HDAC inhibitors for antiplasmodial
activity, model A7 (external accuracy 91%) identified
three hits that were subsequently verified as having potent in vitro
activity against P. falciparum parasites
(IC50 = 6, 71, and 84 nM), with 8 to 51-fold selectivity
for P. falciparum versus human cells.