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

Abstract 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 Match...

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Autores principales:	Bakary N’tji Diallo, Tarryn Swart, Heinrich C. Hoppe, Özlem Tastan Bishop, Kevin Lobb
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5de43a6c752445bb899502702aefff11
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spelling	oai:doaj.org-article:5de43a6c752445bb899502702aefff112021-12-02T14:01:24ZPotential repurposing of four FDA approved compounds with antiplasmodial activity identified through proteome scale computational drug discovery and in vitro assay10.1038/s41598-020-80722-22045-2322https://doaj.org/article/5de43a6c752445bb899502702aefff112021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-80722-2https://doaj.org/toc/2045-2322Abstract 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 IC50 values in the single-digit μM range.Bakary N’tji DialloTarryn SwartHeinrich C. HoppeÖzlem Tastan BishopKevin LobbNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Bakary N’tji Diallo Tarryn Swart Heinrich C. Hoppe Özlem Tastan Bishop Kevin Lobb Potential repurposing of four FDA approved compounds with antiplasmodial activity identified through proteome scale computational drug discovery and in vitro assay
description	Abstract 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 IC50 values in the single-digit μM range.
format	article
author	Bakary N’tji Diallo Tarryn Swart Heinrich C. Hoppe Özlem Tastan Bishop Kevin Lobb
author_facet	Bakary N’tji Diallo Tarryn Swart Heinrich C. Hoppe Özlem Tastan Bishop Kevin Lobb
author_sort	Bakary N’tji Diallo
title	Potential repurposing of four FDA approved compounds with antiplasmodial activity identified through proteome scale computational drug discovery and in vitro assay
title_short	Potential repurposing of four FDA approved compounds with antiplasmodial activity identified through proteome scale computational drug discovery and in vitro assay
title_full	Potential repurposing of four FDA approved compounds with antiplasmodial activity identified through proteome scale computational drug discovery and in vitro assay
title_fullStr	Potential repurposing of four FDA approved compounds with antiplasmodial activity identified through proteome scale computational drug discovery and in vitro assay
title_full_unstemmed	Potential repurposing of four FDA approved compounds with antiplasmodial activity identified through proteome scale computational drug discovery and in vitro assay
title_sort	potential repurposing of four fda approved compounds with antiplasmodial activity identified through proteome scale computational drug discovery and in vitro assay
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/5de43a6c752445bb899502702aefff11
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Potential repurposing of four FDA approved compounds with antiplasmodial activity identified through proteome scale computational drug discovery and in vitro assay

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