Potential repurposing of four FDA approved compounds with antiplasmodial activity identified through proteome scale computational drug discovery and in vitro assay

Diallo, Bakary N’tji; Swart, Tarryn; Hoppe, Heinrich C.; Tastan Bishop, Özlem; Lobb, Kevin

Malaria elimination can benefit from time and cost-efficient approaches for antimalarials such as drug repurposing. In this work, 796 DrugBank compounds were screened against 36 Plasmodium falciparum targets using QuickVina-W. Hits were selected after rescoring using GRaph Interaction Matching (GRIM) and ligand efficiency metrics: surface efficiency index (SEI), binding efficiency index (BEI) and lipophilic efficiency (LipE). They were further evaluated in Molecular dynamics (MD). Twenty-five protein–ligand complexes were finally retained from the 28,656 (36 × 796) dockings. Hit GRIM scores (0.58 to 0.78) showed their molecular interaction similarity to co-crystallized ligands. Minimum LipE (3), SEI (23) and BEI (7) were in at least acceptable thresholds for hits. Binding energies ranged from −6 to −11 kcal/mol. Ligands showed stability in MD simulation with good hydrogen bonding and favorable protein–ligand interactions energy (the poorest being −140.12 kcal/mol). In vitro testing showed 4 active compounds with two having IC(50) values in the single-digit μM range.