Preprint Article Version 2 Preserved in Portico This version is not peer-reviewed

New Workflow Predicts Drug Targets Against SARS-CoV-2 via Metabolic Changes in Infected Cells

Version 1 : Received: 15 March 2022 / Approved: 22 March 2022 / Online: 22 March 2022 (02:40:09 CET)
Version 2 : Received: 27 July 2022 / Approved: 27 July 2022 / Online: 27 July 2022 (10:37:12 CEST)
Version 3 : Received: 13 January 2023 / Approved: 17 January 2023 / Online: 17 January 2023 (01:50:23 CET)

A peer-reviewed article of this Preprint also exists.

Leonidou, N.; Renz, A.; Mostolizadeh, R.; Dräger, A. New Workflow Predicts Drug Targets against SARS-CoV-2 via Metabolic Changes in Infected Cells. PLOS Computational Biology, 2023, 19, e1010903. Leonidou, N.; Renz, A.; Mostolizadeh, R.; Dräger, A. New Workflow Predicts Drug Targets against SARS-CoV-2 via Metabolic Changes in Infected Cells. PLOS Computational Biology, 2023, 19, e1010903.


COVID-19 has been characterized as one of the deadliest respiratory diseases, and the emergence of SARS-CoV-2 caught the pharmaceutical industry and the drug development communities off guard. Identifying potential antiviral targets is of great concern, and one way to detect them is by analyzing metabolic changes in infected cells. In this study, we present a novel workflow to predict robust druggable targets against emerging RNA viruses using metabolic networks and information of the viral structure and its genome sequence. For this purpose, we implemented pymCADRE, a tool to create metabolic models using gene expression data, and used this to reconstruct a metabolic network of the human bronchial epithelial cells. We observed that pymCADRE reduces the computational time when flux variability analysis is employed for internal optimizations. Subsequently, we created a fully automated computational tool, named PREDICATE, which analyses one or more nucleotide sequences, introduces given amino acid mutations, and simulates in silico viral infections. Moreover, it predicts a set of host reactions, which, when constrained, inhibit the virus production while preserving the host’s optimal state. In the context of SARS-CoV-2, we applied this tool to our metabolic network of bronchial epithelial cells and identified enzymatic reactions with inhibitory effects. From the list of the reported targets, the most promising one was the Nucleoside Diphosphate Kinase, whose inhibitors have already been reported in the literature. Finally, we computationally tested the robustness of our targets in all currently known variants of concern, verifying the inhibitory effect of our target enzyme against SARS-CoV-2. Focusing on the metabolic fluxes of infected cells, we aim at applying our workflow and methods for rapid hypothesis-driven identification of potentially exploitable antivirals to efficiently prevent future pandemics concerning various viruses and host cell types.

Supplementary and Associated Material


host-virus interactions; tissue-specific model; COVID-19; SARS-CoV-2; antiviral targets; flux balance analysis; flux variability analysis; reaction knockout; host-derived enforcement; metabolic modeling; virus mutations; nucleoside diphosphate kinase; software engineering; Python


Biology and Life Sciences, Biology and Biotechnology

Comments (1)

Comment 1
Received: 27 July 2022
Commenter: Nantia Leonidou
Commenter's Conflict of Interests: Author
Comment: - Lines 226-229 have been moved at the end of the section - Lipids have been included in the viral biomass function and details can be found in the Materials and Methods section - Lines 273-274 have been removed - Previous work has been added in the introduction and discussion part. Lines 112-121, 1046-1048, 344, 711-712, 162-163  - Lines 353-354  have been removed to avoid repetitions.  - Table 2 has been updated with complete reactions names - Lines 278-285 have been moved to the Materials and Methods section
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