Potential repurposing of four FDA approved compounds with antiplasmodial activity identified through proteome scale computational drug discovery and in vitro assay
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...
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Published in | Scientific reports Vol. 11; no. 1; pp. 1413 - 15 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
14.01.2021
Nature Publishing Group Nature Portfolio |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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ISSN: | 2045-2322 2045-2322 |
DOI: | 10.1038/s41598-020-80722-2 |