Exploration of Antiplasmodium Chemical Space Identifies New Inhibitors of β-Hematin Formation from Areas of Enrichment

Abstract

The Tres Cantos Antimalarial Set (TCAMS) library is a valuable resource for identifying hits for the antimalarial pipeline. We used principal component analysis (PCA) to explore this tranche of chemical space. Applying a set of 17 two-dimensional (2D) molecular descriptors, the chemical space was mapped in 2D PC space. Thereafter, the locations of known inhibitors and noninhibitors of synthetic hemozoin (β-hematin) formation, a well-established drug target during the asexual blood stage of the Plasmodium falciparum parasite life cycle, were superimposed onto the 2D map and counted. Within the +PC1, −PC2 quadrant, an area of enrichment emerged that could be used to predict the activity of test compounds. A subset of 861 TCAMS compounds (45 inhibitors and 816 noninhibitors) yielded a 27% hit rate when filtered using the enrichment map. Thereafter, 81 diverse compounds with predicted activity were purchased and 20 (25%) were active. B37, which contains a pyrido carbazole scaffold, demonstrated potent β-hematin formation inhibitory activity (IC₅₀ = 6.4 ± 0.19 μM) as well as noteworthy activity against the chloroquine-sensitive NF54 strain (IC₅₀ = 0.32 ± 0.03 μM). The PCA enrichment map for β-hematin inhibition is a useful tool for rapid identification of potential hit compounds and may be extended in the future to other antimalarial targets.