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Drug repurposing improves disease targeting 11-fold and can be augmented by network module targeting, applied to COVID-19.

ABSTRACT: This analysis presents a systematic evaluation of the extent of therapeutic opportunities that can be obtained from drug repurposing by connecting drug targets with disease genes. When using FDA-approved indications as a reference level we found that drug repurposing can offer an average of an 11-fold increase in disease coverage, with the maximum number of diseases covered per drug being increased from 134 to 167 after extending the drug targets with their high confidence first neighbors. Additionally, by network analysis to connect drugs to disease modules we found that drugs on average target 4 disease modules, yet the similarity between disease modules targeted by the same drug is generally low and the maximum number of disease modules targeted per drug increases from 158 to 229 when drug targets are neighbor-extended. Moreover, our results highlight that drug repurposing is more dependent on target proteins being shared between diseases than on polypharmacological properties of drugs. We apply our drug repurposing and network module analysis to COVID-19 and show that Fostamatinib is the drug with the highest module coverage.

SUBMITTER: Rivero-Garcia I

PROVIDER: S-EPMC8526804 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Drug repurposing improves disease targeting 11-fold and can be augmented by network module targeting, applied to COVID-19.

Rivero-García Inés I Castresana-Aguirre Miguel M Guglielmo Luca L Guala Dimitri D Sonnhammer Erik L L ELL

Scientific reports 20211019 1

This analysis presents a systematic evaluation of the extent of therapeutic opportunities that can be obtained from drug repurposing by connecting drug targets with disease genes. When using FDA-approved indications as a reference level we found that drug repurposing can offer an average of an 11-fold increase in disease coverage, with the maximum number of diseases covered per drug being increased from 134 to 167 after extending the drug targets with their high confidence first neighbors. Addit ...[more]

PMID: 34667255

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Project description:The COVID-19 pandemic caused by the SARS-CoV-2 virus has greatly affected global health. Emerging evidence suggests a complex interplay between Alzheimer's disease (AD), diabetes (DM), and COVID-19. Given COVID-19's involvement in the increased risk of other diseases, there is an urgent need to identify novel targets and drugs to combat these interconnected health challenges. Lysophosphatidic acid receptors (LPARs), belonging to the G protein-coupled receptor family, have been implicated in various pathological conditions, including inflammation. In this regard, the study aimed to investigate the involvement of LPARs (specifically LPAR1, 3, 6) in the tri-directional relationship between AD, DM, and COVID-19 through network analysis, as well as explore the therapeutic potential of selected anti-AD, anti-DM drugs as LPAR, SPIKE antagonists. We used the Coremine Medical database to identify genes related to DM, AD, and COVID-19. Furthermore, STRING analysis was used to identify the interacting partners of LPAR1, LPAR3, and LPAR6. Additionally, a literature search revealed 78 drugs on the market or in clinical studies that were used for treating either AD or DM. We carried out docking analysis of these drugs against the LPAR1, LPAR3, and LPAR6. Furthermore, we modeled the LPAR1, LPAR3, and LPAR6 in a complex with the COVID-19 spike protein and performed a docking study of selected drugs with the LPAR-Spike complex. The analysis revealed 177 common genes implicated in AD, DM, and COVID-19. Protein-protein docking analysis demonstrated that LPAR (1,3 & 6) efficiently binds with the viral SPIKE protein, suggesting them as targets for viral infection. Furthermore, docking analysis of the anti-AD and anti-DM drugs against LPARs, SPIKE protein, and the LPARs-SPIKE complex revealed promising candidates, including lupron, neflamapimod, and nilotinib, stating the importance of drug repurposing in the drug discovery process. These drugs exhibited the ability to bind and inhibit the LPAR receptor activity and the SPIKE protein and interfere with LPAR-SPIKE protein interaction. Through a combined network and targeted-based therapeutic intervention approach, this study has identified several drugs that could be repurposed for treating COVID-19 due to their expected interference with LPAR(1, 3, and 6) and spike protein complexes. In addition, it can also be hypothesized that the co-administration of these identified drugs during COVID-19 infection may not only help mitigate the impact of the virus but also potentially contribute to the prevention or management of post-COVID complications related to AD and DM.

Dataset Information

Drug repurposing improves disease targeting 11-fold and can be augmented by network module targeting, applied to COVID-19.

Publications

Drug repurposing improves disease targeting 11-fold and can be augmented by network module targeting, applied to COVID-19.

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