1 research outputs found
Identification of Novel Antimalarial Chemotypes via Chemoinformatic Compound Selection Methods for a High-Throughput Screening Program against the Novel Malarial Target, PfNDH2: Increasing Hit Rate via Virtual Screening Methods
Malaria is responsible for approximately 1 million deaths
annually; thus, continued efforts to discover new antimalarials are
required. A HTS screen was established to identify novel inhibitors
of the parasite's mitochondrial enzyme NADH:quinone oxidoreductase
(PfNDH2). On the basis of only one known inhibitor of this enzyme,
the challenge was to discover novel inhibitors of PfNDH2 with diverse
chemical scaffolds. To this end, using a range of ligand-based chemoinformatics
methods, ∼17000 compounds were selected from a commercial library
of ∼750000 compounds. Forty-eight compounds were identified
with PfNDH2 enzyme inhibition IC<sub>50</sub> values ranging from
100 nM to 40 μM and also displayed exciting whole cell antimalarial
activity. These novel inhibitors were identified through sampling
16% of the available chemical space, while only screening 2% of the
library. This study confirms the added value of using multiple ligand-based
chemoinformatic approaches and has successfully identified novel distinct
chemotypes primed for development as new agents against malaria