Original Research
Drug repurposing for COVID-19 via knowledge graph completion

https://doi.org/10.1016/j.jbi.2021.103696Get rights and content
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Highlights

  • Developed a novel drug repurposing approach integrating literature-based discovery and knowledge graph completion.

  • Constructed a biomedical knowledge graph for drug repurposing on PubMed and COVID-19 research literature.

  • Evaluated five state-of-the-art, neural knowledge graph completion methods for the task of drug repurposing.

  • Generated plausible hypotheses regarding mechanisms of proposed drugs using discovery patterns.

  • Proposed novel drugs that were not published in the literature and are not in clinicaltrials.gov.

Abstract

Objective

To discover candidate drugs to repurpose for COVID-19 using literature-derived knowledge and knowledge graph completion methods.

Methods

We propose a novel, integrative, and neural network-based literature-based discovery (LBD) approach to identify drug candidates from PubMed and other COVID-19-focused research literature. Our approach relies on semantic triples extracted using SemRep (via SemMedDB). We identified an informative and accurate subset of semantic triples using filtering rules and an accuracy classifier developed on a BERT variant. We used this subset to construct a knowledge graph, and applied five state-of-the-art, neural knowledge graph completion algorithms (i.e., TransE, RotatE, DistMult, ComplEx, and STELP) to predict drug repurposing candidates. The models were trained and assessed using a time slicing approach and the predicted drugs were compared with a list of drugs reported in the literature and evaluated in clinical trials. These models were complemented by a discovery pattern-based approach.

Results

Accuracy classifier based on PubMedBERT achieved the best performance (F1 = 0.854) in identifying accurate semantic predications. Among five knowledge graph completion models, TransE outperformed others (MR = 0.923, Hits@1 = 0.417). Some known drugs linked to COVID-19 in the literature were identified, as well as others that have not yet been studied. Discovery patterns enabled identification of additional candidate drugs and generation of plausible hypotheses regarding the links between the candidate drugs and COVID-19. Among them, five highly ranked and novel drugs (i.e., paclitaxel, SB 203580, alpha 2-antiplasmin, metoclopramide, and oxymatrine) and the mechanistic explanations for their potential use are further discussed.

Conclusion

We showed that a LBD approach can be feasible not only for discovering drug candidates for COVID-19, but also for generating mechanistic explanations. Our approach can be generalized to other diseases as well as to other clinical questions. Source code and data are available at https://github.com/kilicogluh/lbd-covid.

Keywords

COVID-19
Drug repurposing
Knowledge graph completion
Literature-based discovery
Text mining

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1

Authors contributed equally.