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

• Published in: Scientific reports Vol. 11; no. 1; pp. 1413 - 15
• Main Authors: Diallo, Bakary N’tji, Swart, Tarryn, Hoppe, Heinrich C., Tastan Bishop, Özlem, Lobb, Kevin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/114/2163; 631/154/1435/2418; 631/154/309/2144; Antimalarials - chemistry; Antiprotozoal agents; Computer applications; Drug Repositioning; Efficiency; Humanities and Social Sciences; Hydrogen bonding; Ligands; Lipophilic; Malaria; Molecular Docking Simulation; Molecular Dynamics Simulation; multidisciplinary; Plasmodium falciparum; Plasmodium falciparum - chemistry; Proteomes; Protozoan Proteins - chemistry; Science; Science (multidisciplinary); Vector-borne diseases
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-80722-2

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.