PLOS ONE · 10 authors, 3 centres
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This study virtually screened 4193 FDA-approved drugs against 24 SARS-CoV2 proteins and identified 15 multi-targeting drugs, including dihydroergotamine and ergotamine, which bind to up to 8 viral targets. The top-scoring drugs were primarily indicated for neurological disorders, cancer, pain, and bacterial infections. These findings suggest that polypharmacological drug repurposing could offer effective multi-target therapies against COVID-19.
**Background:** The COVID-19 pandemic, caused by SARS-CoV2, has highlighted the urgent need for effective therapeutics. Drug repurposing offers a rapid strategy to identify existing drugs for new indications. This study employed a polypharmacology-guided virtual screening approach to identify FDA-approved drugs that can simultaneously target multiple SARS-CoV2 proteins, aiming to overcome challenges like viral mutation and drug resistance.
**Methods:** The authors selected 24 SARS-CoV2 protein targets (NSP1-10, NSP12-16, envelope, membrane, nucleoprotein, spike, ORF3a, ORF6, ORF7a, ORF8, ORF9b) based on their roles in viral entry, replication, and transcription. Protein structures were obtained from the RCSB PDB (20 targets) or modeled using I-TASSER (4 targets: NSP4, NSP6, M, ORF6). A library of 4193 unique FDA-approved drugs was compiled from DrugBank and DrugCentral. Virtual screening was performed using AutoDock Vina 1.1.2. Docking scores were used to classify drugs into active (above a target-specific threshold) and inactive groups. The top 10 and bottom 10 drugs per target were analyzed for therapeutic indications. Binding affinities were validated using three additional programs: MT-DTI, SwissDock, and iGEMDOCK. Polypharmacological analysis identified drugs interacting with ≥3 SARS-CoV2 targets. For these 15 multi-targeting drugs, gene enrichment analysis (ShinyGO) and KEGG pathway analysis (Metascape) were performed on their known human targets (26 genes) to identify biological pathways relevant to SARS-CoV2 infection.
**Key Results:** The average maximum docking score for each protein ranged from -5.0 to -7.0 kcal/mol. Across all targets, an average of 53.5% of drugs were classified as active. Among the top 10 drugs per target, 162 unique drugs were identified, with 39 drugs appearing multiple times. The top-scoring drugs showed therapeutic indications primarily for central nervous system disorders, followed by immunological disorders, cancer, pain, and viral/bacterial diseases. The highest docking score observed was -12.6 kcal/mol for paritaprevir (hepatitis C drug) with nucleoprotein, and -11.8 kcal/mol for sonidegib (anticancer) with NSP16. Polypharmacological analysis revealed 15 drugs interacting with ≥3 SARS-CoV2 targets. Dihydroergotamine and ergotamine each bound to 8 targets (membrane, nucleoprotein, NSP2, NSP12, ORF3a, ORF9b, and others). Bisdequalinium chloride, midostaurin, temoporfin, tirilazad, and venetoclax each interacted with 5 targets. Key interacting residues included hydrophobic amino acids (ILE, LEU, ALA, ARG, VAL) and polar residues (SER, ASN, GLN, THR) involved in hydrogen bonding. Gene enrichment analysis showed that the majority of the 26 genes were involved in biological processes like regulation of biological quality, with the most significant pathway being phospholipase C-activating G protein-coupled receptor (GPCR) signaling. Cellular component analysis highlighted the integral component of plasma membrane, and molecular function analysis emphasized molecular transducer activity. KEGG pathway analysis identified two densely connected protein clusters, including 12 genes (e.g., ADRA1A, HTR2A, OPRM1) involved in GPCR activity, MAPK cascade, and cell signaling. The known COVID-19 drugs remdesivir and baricitinib showed good binding scores (e.g., remdesivir with NSP12: -7.0 kcal/mol; baricitinib with membrane: -7.9 kcal/mol) but were not among the top 10 for any target.
**Clinical Implications:** This study identifies several FDA-approved drugs with polypharmacological potential against SARS-CoV2, offering a promising strategy to combat viral resistance through multi-target inhibition. Drugs originally indicated for neurological disorders (tirilazad), pain (dihydroergotamine, ergotamine), cancer (midostaurin, venetoclax, temoporfin), and bacterial infections (bisdequalinium chloride) may be repurposed as anti-SARS-CoV2 agents. The identified common scaffolds (e.g., 1-benzazepine, decalin) and key interacting residues provide a foundation for designing novel, high-affinity inhibitors. The pathway analysis underscores the importance of GPCR signaling and plasma membrane integrity in SARS-CoV2 infection, suggesting that drugs modulating these pathways could have therapeutic benefit. However, these findings are based on computational predictions and require experimental validation in vitro and in vivo before clinical application.