Structure-based virtual screening against multiple Plasmodium falciparum kinases reveals antimalarial compounds

Area of Science:

• Drug discovery and development
• Parasitology
• Medicinal chemistry

Background:

• Emerging resistance to frontline antimalarial drugs causes significant mortality, with 619,000 deaths in 2021.
• Drug resistance arises from mutations in drug targets, which often incur a fitness cost, making simultaneous mutations in multiple targets unlikely.

Purpose of the Study:

• To identify multitargeting inhibitors against six Plasmodium falciparum (Pf) kinases using High Throughput Virtual Screening.
• To evaluate the potential of these compounds to overcome existing antimalarial drug resistance.

Main Methods:

• High Throughput Virtual Screening (HTVS) was employed to screen for inhibitors targeting six validated Plasmodium falciparum kinases.
• Molecular dynamic simulations were performed on the top six predicted complexes to assess interaction stability.
• Hierarchical clustering was used to analyze the structural divergence of identified compounds from existing antimalarials.
• In vitro parasite growth inhibition assays were conducted to validate the efficacy of the top hits.

Main Results:

• The study identified 21 multitargeting hits against the selected Plasmodium falciparum kinases.
• Molecular dynamic simulations confirmed stable interactions for the top six complexes, including Myricetin-MAP2, Quercetin-CDPK4, Myricetin-TMK, Quercetin-PKG, Salidroside-PK5, and Salidroside-PI4K.
• Hierarchical clustering indicated that the identified compounds are structurally distinct from current antimalarials, suggesting a lower likelihood of cross-resistance.
• In vitro assays demonstrated significant antimalarial activity, with quercetin and myricetin showing IC50 values of 1.84 µM and 3.93 µM, respectively.

Conclusions:

• Multitargeting inhibitors represent a viable strategy to combat Plasmodium falciparum drug resistance.
• The identified compounds, particularly quercetin and myricetin, show promise as novel antimalarial drug candidates.
• Structural novelty of these compounds suggests a reduced risk of cross-resistance with existing therapies.