Integrative resource for network-based investigation of COVID-19 combinatorial drug repositioning and mechanism of action

Abstract

An effective monotherapy to target the complex and multifactorial pathology of SARS-CoV-2 infection poses a challenge to drug repositioning, which can be improved by combination therapy. We developed an online network pharmacology-based drug repositioning platform, COVID-CDR ( http://vafaeelab.com/COVID19repositioning.html ), that enables a visual and quantitative investigation of the interplay between the drug primary targets and the SARS-CoV-2–host interactome in the human protein-protein interaction network. COVID-CDR prioritizes drug combinations with potential to act synergistically through different, yet potentially complementary pathways. It provides the options for understanding multi-evidence drug-pair similarity scores along with several other relevant information on individual drugs or drug pairs. Overall, COVID-CDR is the first-of-its-kind online platform that provides a systematic approach for pre-clinical in silico investigation of combination therapies for treating COVID-19 at the fingertips of the clinicians and researchers.

Human Group IIA Phospholipase A2—Three Decades on from Its Discovery

“…Additionally, dramatic advances in omics technologies resulting in accessible and reliable generation of lipidomics, proteomics and transcriptomics data allow detailed examination of the effect of manipulation of hGIIA function on global metabolism. This coupled with emerging advances in network pharmacology approaches [ 154 , 155 ] will enable the integration of complex omics data as well as known biochemistry of the metabolic pathways and cellular interactions into testable in silico models to assess the system-level effect and efficacy of hGIIA inhibitors in different cellular and tissue contexts. Further, advances in imaging techniques coupled with omics technologies in both physiological and pathological states [ 156 , 157 , 158 ] have created opportunities to examine the dynamic intracellular organization of hGIIA and its protein interaction partners to explore the temporal and spatial organization of the enzyme in cellular and tissue contexts.…”

A comprehensive review of artificial intelligence and network based approaches to drug repurposing in Covid-19

“… Title Datasets used Repurposed Drugs Evaluation Criteria Tools used Ref. 1 Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2 GEO, CMAP, DrugBank, Uniprot 16 Drugs And 4 Drug combination Network Proximity measures, Gene enrichment Gephi, Enricher, KEGG, GO [164] 2 Designing a Network Proximity-Based Drug Repurposing Strategy for COVID-19 DrugBank, GEO, GeneCards – Network proximity, Functional analysis VarElect [169] 3 SAveRUNNER: A network-based algorithm for drug repurposing and its application to COVID-19 DrugBank, Uniprot, TTD, Phenopedia, CMAP 24 Drugs, 5 Drug combinations Network Proximity measures, Gene enrichment, ROC performance Curve KEGG Pathway analysis, GSEA [170] 4 Network-Based Approach to Repurpose Approved Drugs for COVID-19 by Integrating GWAS and Text Mining Data GWAS, LINCS, DrugBank 13 Drugs – GWAS [175] 5 Network medicine framework for identifying drug-repurposing opportunities for COVID-19 13 Datasets, DrugBank, STRING 989 Drugs, 77 Validated in VeroE6 Cells, 76/77 validated in Human Cells Network proximity, network diffusion, Network AI Experimental, Ensembl algorithmic prediction [176] 6 Integrative resource for network-based investigation of COVID-19 combinatorial drug repositioning and mechanism of action STRING, DrugBank, ChEMBL, PubChem, GO, KEGG, ClinicalTrials.gov, SIDER, Uniprot, SNAP 867 FDA approved Drugs and Combinations Proximity, Gene ontology – [177] 7 A Network Medicine Approach to Investigation and Population-based Validation of Disease Manifestations and Drug Repurposing for COVID-19 CMAP, DrugBank, STRING, GEO 34 Drugs Network Proximity meas...…”

“…The ability to repurpose the drug combination was hampered by the availability of large range of possible pairs. To address this gap a study was done in [177] where an integrative network pharmacology inspired web-based tool named COVID-CDR was developed for in-silico repurposing of the drug combinations. Deployed web-based tool can visualize the interaction in the interactome on the cellular level involved in the mechanism of action of the drugs involved.…”

A Review on Graph Neural Networks for Predicting Synergistic Drug Combinations

“…However, the search for effective combinations is hindered by the sheer number of potential drug pairs, leading to a combinatorial explosion [4,5]. It is, therefore, infeasible to experimentally screen the enormous search space of all possible drug combinations.…”