Small Molecule Kinase Inhibitors with In Vitro β-Hematin Formation and Plasmodium falciparum Protein Kinase G...

Area of Science:

• Medicinal Chemistry
• Parasitology
• Computational Biology

Background:

• Malaria remains a significant global health threat, necessitating novel therapeutic strategies.
• Targeting Plasmodium falciparum beta-hematin formation and cGMP-dependent protein kinase (PfPKG) offers potential antimalarial pathways.
• Existing antimalarials face challenges due to resistance and side effects.

Purpose of the Study:

• To identify novel dual-acting inhibitors against beta-hematin formation and PfPKG in Plasmodium falciparum.
• To screen the BioVision Protein Kinase Inhibitor library using computational methods.
• To evaluate the potency and dual-activity profile of identified hit compounds.

Main Methods:

• Utilized molecular docking and machine learning for high-throughput virtual screening.
• Assessed inhibition of beta-hematin formation and PfPKG activity.
• Quantified compound potency using IC50 values.

Main Results:

• Identified three compounds with dual activity against beta-hematin formation and PfPKG.
• Derazantinib exhibited the most potent dual inhibition (88 µM for beta-hematin, 0.160 µM for PfPKG).
• Pazopanib and afatinib demonstrated moderate dual activity.

Conclusions:

• Derazantinib represents a promising lead compound for developing new antimalarials targeting multiple pathways.
• Computational screening effectively identified dual-acting inhibitors against key Plasmodium falciparum targets.
• Further investigation of these compounds could lead to novel malaria treatment options.