Small Molecule Kinase Inhibitors with In Vitro β‐Hematin Formation and <i>Plasmodium falciparum</i> Protein Kinase G Inhibitory Activity Identified Using Machine Learning

Abstract

Using a combination of molecular docking and machine learning, the BioVision Protein Kinase Inhibitor library was screened for potential inhibitors with dual activity against two Plasmodium falciparum targets, β-hematin (synthetic hemozoin) formation and cGMP-dependent protein kinase (PfPKG). Three compounds with promising activity against both targets were identified. Derazantinib is the most potent hit compound with IC₅₀ values of 88 µM for inhibition of β-hematin formation (compared to 22 μM for chloroquine) and 0.160 µM against PfPKG. Pazopanib (β-hematin IC₅₀: 219 µM and PfPKG IC₅₀: 0.330 µM) and afatinib (234 and 2.61 µM, respectively) showed more moderate activity profiles against both targets.