Random Forest Model Predictions Afford Dual-Stage Antimalarial Agents.

The need for novel antimalarials is apparent given the continuing disease burden worldwide, despite significant drug discovery advances from the bench to the bedside. In particular, small-molecule agents with potent efficacy against both the liver and blood stages of Plasmodium parasite infection are critical for clinical settings as they would simultaneously prevent and treat malaria with a reduced selection pressure for resistance. While experimental screens for such dual-stage inhibitors have been conducted, the time and cost of these efforts limit their scope. Here, we have focused on leveraging machine learning approaches to discover novel antimalarials with such properties. A random forest modeling approach was taken to predict small molecules with in vitro efficacy versus liver-stage Plasmodium berghei parasites and a lack of human liver cell cytotoxicity. Empirical validation of the model was achieved with the realization of hits with liver-stage efficacy after prospective scoring of a commercial diversity library and consideration of structural diversity. A subset of these hits also demonstrated promising blood-stage Plasmodium falciparum efficacy. These 18 validated dual-stage antimalarials represent novel starting points for drug discovery and mechanism of action studies with significant potential for seeding a new generation of therapies.

Biomimetic strategies to produce catalytically reactive CuS nanodisks.

Copper sulfide materials have diverse applications from cancer therapy to environmental remediation due to their narrow bandgap and easily tuned plasmon. The synthesis of these materials often involves toxic reagents and harsh conditions where biomimetic methods may provide opportunities to produce these structures under sustainable conditions. To explore this capability, simple amino acids were exploited as biological ligands for the ambient synthesis of CuS materials. Using an aqueous-based approach, CuS nanodisks were prepared using acid-containing amino acid molecules that stabilize the materials against bulk aggregation. These structures were fully characterized by UV-vis analysis, transmission electron microscopy, dynamic light scattering, atomic force microscopy, selected area electron diffraction, and X-ray diffraction, which confirmed the formation of CuS. The materials possessed a vibrant plasmon band in the near IR region and demonstrated enhanced photocatalytic reactivity for the advanced oxidation of organic dyes in water. These results demonstrate a room temperature synthetic route to optically important materials, which could have important application in catalysis, optics, nanomedicine, etc.