Faculty Opinions recommendation of Multiscale interactome analysis coupled with off-target drug predictions reveals drug repurposing candidates for human coronavirus disease.

The COVID-19 pandemic has led to an urgent need for the identification of new antiviral drug therapies that can be rapidly deployed to treat patients with this disease. COVID-19 is caused by infection with the human coronavirus SARS-CoV-2. We developed a computational approach to identify new antiviral drug targets and repurpose clinically-relevant drug compounds for the treatment of COVID-19. Our approach is based on graph convolutional networks (GCN) and involves multiscale host-virus interactome analysis coupled to off-target drug predictions. Cell-based experimental assessment reveals several clinically-relevant repurposing drug candidates predicted by the in silico analyses to have antiviral activity against human coronavirus infection. In particular, we identify the MET inhibitor capmatinib as having potent and broad antiviral activity against several coronaviruses in a MET-independent manner, as well as novel roles for host cell proteins such as IRAK1/4 in supporting human coronavirus infection, which can inform further drug discovery studies.

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Multiscale interactome analysis coupled with off-target drug predictions reveals drug repurposing candidates for human coronavirus disease

Scientific Reports ◽

10.1038/s41598-021-02432-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Michael G. Sugiyama ◽

Haotian Cui ◽

Dar’ya S. Redka ◽

Mehran Karimzadeh ◽

Edurne Rujas ◽

...

Keyword(s):

Antiviral Activity ◽

Drug Targets ◽

Respiratory Infections ◽

Antiviral Drug ◽

Drug Repurposing ◽

Human Coronavirus ◽

Independent Manner ◽

Convolutional Networks ◽

Target Drug ◽

Coronavirus Infection

AbstractThe COVID-19 pandemic has highlighted the urgent need for the identification of new antiviral drug therapies for a variety of diseases. COVID-19 is caused by infection with the human coronavirus SARS-CoV-2, while other related human coronaviruses cause diseases ranging from severe respiratory infections to the common cold. We developed a computational approach to identify new antiviral drug targets and repurpose clinically-relevant drug compounds for the treatment of a range of human coronavirus diseases. Our approach is based on graph convolutional networks (GCN) and involves multiscale host-virus interactome analysis coupled to off-target drug predictions. Cell-based experimental assessment reveals several clinically-relevant drug repurposing candidates predicted by the in silico analyses to have antiviral activity against human coronavirus infection. In particular, we identify the MET inhibitor capmatinib as having potent and broad antiviral activity against several coronaviruses in a MET-independent manner, as well as novel roles for host cell proteins such as IRAK1/4 in supporting human coronavirus infection, which can inform further drug discovery studies.

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Rational Discovery of Dual-Action Multi-Target Kinase Inhibitor for Precision Anti-Cancer Therapy Using Structural Systems Pharmacology

10.1101/465054 ◽

2018 ◽

Author(s):

Hansaim Lim ◽

Di He ◽

Yue Qiu ◽

Patrycja Krawczuk ◽

Xiaoru Sun ◽

...

Keyword(s):

Machine Learning ◽

Heart Failure ◽

Drug Resistance ◽

Drug Repurposing ◽

Target Drug ◽

Genome Wide ◽

Anti Cancer ◽

Dual Action ◽

Target Screening ◽

Genome Scale

AbstractAlthough remarkable progresses have been made in the cancer treatment, existing anti-cancer drugs are associated with increasing risk of heart failure, variable drug response, and acquired drug resistance. To address these challenges, for the first time, we develop a novel genome-scale multi-target screening platform 3D-REMAP that integrates data from structural genomics and chemical genomics as well as synthesize methods from structural bioinformatics, biophysics, and machine learning. 3D-REMAP enables us to discover marked drugs for dual-action agents that can both reduce the risk of heart failure and present anti-cancer activity. 3D-REMAP predicts that levosimendan, a drug for heart failure, inhibits serine/threonine-protein kinase RIOK1 and other kinases. Subsequent experiments confirm this prediction, and suggest that levosimendan is active against multiple cancers, notably lymphoma, through the direct inhibition of RIOK1 and RNA processing pathway. We further develop machine learning models to identify cancer cell-lines and patients that may respond to levosimendan. Our findings suggest that levosimendan can be a promising novel lead compound for the development of safe and effective multi-targeted cancer therapy, and demonstrate the potential of genome-wide multi-target screening in designing polypharmacology and drug repurposing for precision medicine.Author SummaryMulti-target drug design (a.k.a targeted polypharmacology) has emerged as a new strategy for discovering novel therapeutics that can enhance therapeutic efficacy and overcome drug resistance in tackling multi-genic diseases such as cancer. However, it is extremely challenging for conventional computational tools that are either receptor-based or ligand-based to screen compounds for selectively targeting multiple receptors. Existing multi-target drug design mainly focuses on compound screening against receptors within the same gene family but not across different gene families. Here, we develop a new computational tool 3D-REMAP that enables us to identify chemical-protein interactions across fold space on a genome scale. The genome-scale chemical-protein interaction network allows us to discover dual-action drugs that can bind to two types of targets simultaneously, one for mitigating side effect and another for enhancing the therapeutic effect. Using 3D-REMAP, we predict and subsequently experiments validate that levosimendan, a drug for heart failure, is active against multiple cancers, notably, lymphoma. This study demonstrates the potential of genome-wide multi-target screening in designing polypharmacology and drug repurposing for precision medicine.

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Main Protease Inhibitors and Drug Surface Hotspot for the Treatment of COVID-19: Drug Repurposing and Molecular Docking Approach

10.26434/chemrxiv.12118857.v1 ◽

2020 ◽

Author(s):

Mahmudul Hasan ◽

Md Sorwer Alam Parvez ◽

Kazi Faizul Azim ◽

Abdus Shukur Imran ◽

Topu Raihan ◽

...

Keyword(s):

Molecular Docking ◽

Drug Repurposing ◽

Pharmacokinetic Parameters ◽

The Novel ◽

Drug Candidates ◽

Target Drug ◽

Global Pandemic ◽

Main Protease ◽

Docking Approach ◽

Repurposed Drugs

<div>The world is facing an unprecedented global pandemic caused by the novel SARS-CoV-2. In the absence</div><div>of a specific therapeutic agent to treat COVID-19 patients, the present study aimed to virtually screen out</div><div>the effective drug candidates from the approved main protease protein (MPP) inhibitors and their</div><div>derivatives for the treatment of SARS-CoV-2. Here, drug repurposing and molecular docking were</div><div>employed to screen approved MPP inhibitors and their derivatives. The approved MPP inhibitors against</div><div>HIV and HCV were prioritized, whilst hydroxychloroquine, favipiravir, remdesivir, and alpha-ketoamide</div><div>were studied as control. The target drug surface hotspot was also investigated through the molecular</div><div>docking technique. ADME analysis was conducted to understand the pharmacokinetics and drug-likeness</div><div>of the screened MPP inhibitors. The result of this study revealed that Paritaprevir (-10.9 kcal/mol), and its</div><div>analog (CID 131982844)(-16.3 kcal/mol) showed better binding affinity than the approved MPP inhibitor</div><div>compared in this study including favipiravir, remdesivir, and alpha-ketoamide. A comparative study among</div><div>the screened putative MPP inhibitors revealed that amino acids T25, T26, H41, M49, L141, N142, G143,</div><div>C145, H164, M165, E166, D187, R188, and Q189 are at critical positions for becoming the surface hotspot</div><div>in the MPP of SARS-CoV-2. The study also suggested that paritaprevir and its' analog (CID 131982844),</div><div>may be effective against SARS-CoV-2 as these molecules had the common drug-surface hotspots on the</div><div>main protease protein of SARS-CoV-2. Other pharmacokinetic parameters also indicate that paritaprevir</div><div>and its top analog (CID 131982844) will be either similar or better-repurposed drugs than already approved</div><div>MPP inhibitors. </div><div><br></div>

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SAveRUNNER: A network-based algorithm for drug repurposing and its application to COVID-19

PLoS Computational Biology ◽

10.1371/journal.pcbi.1008686 ◽

2021 ◽

Vol 17 (2) ◽

pp. e1008686

Author(s):

Giulia Fiscon ◽

Federica Conte ◽

Lorenzo Farina ◽

Paola Paci

Keyword(s):

Drug Targets ◽

De Novo ◽

Drug Repositioning ◽

Drug Repurposing ◽

Gene Set Enrichment Analysis ◽

Thrombin Inhibitors ◽

New Combination ◽

Human Coronavirus ◽

Human Interactome ◽

Off Label

The novelty of new human coronavirus COVID-19/SARS-CoV-2 and the lack of effective drugs and vaccines gave rise to a wide variety of strategies employed to fight this worldwide pandemic. Many of these strategies rely on the repositioning of existing drugs that could shorten the time and reduce the cost compared to de novo drug discovery. In this study, we presented a new network-based algorithm for drug repositioning, called SAveRUNNER (Searching off-lAbel dRUg aNd NEtwoRk), which predicts drug–disease associations by quantifying the interplay between the drug targets and the disease-specific proteins in the human interactome via a novel network-based similarity measure that prioritizes associations between drugs and diseases locating in the same network neighborhoods. Specifically, we applied SAveRUNNER on a panel of 14 selected diseases with a consolidated knowledge about their disease-causing genes and that have been found to be related to COVID-19 for genetic similarity (i.e., SARS), comorbidity (e.g., cardiovascular diseases), or for their association to drugs tentatively repurposed to treat COVID-19 (e.g., malaria, HIV, rheumatoid arthritis). Focusing specifically on SARS subnetwork, we identified 282 repurposable drugs, including some the most rumored off-label drugs for COVID-19 treatments (e.g., chloroquine, hydroxychloroquine, tocilizumab, heparin), as well as a new combination therapy of 5 drugs (hydroxychloroquine, chloroquine, lopinavir, ritonavir, remdesivir), actually used in clinical practice. Furthermore, to maximize the efficiency of putative downstream validation experiments, we prioritized 24 potential anti-SARS-CoV repurposable drugs based on their network-based similarity values. These top-ranked drugs include ACE-inhibitors, monoclonal antibodies (e.g., anti-IFNγ, anti-TNFα, anti-IL12, anti-IL1β, anti-IL6), and thrombin inhibitors. Finally, our findings were in-silico validated by performing a gene set enrichment analysis, which confirmed that most of the network-predicted repurposable drugs may have a potential treatment effect against human coronavirus infections.

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Anti-HIV drug repurposing against SARS-CoV-2

RSC Advances ◽

10.1039/d0ra01899f ◽

2020 ◽

Vol 10 (27) ◽

pp. 15775-15783 ◽

Cited By ~ 22

Author(s):

Peng Sang ◽

Shu-Hui Tian ◽

Zhao-Hui Meng ◽

Li-Quan Yang

Keyword(s):

Public Health ◽

Severe Acute Respiratory Syndrome ◽

Drug Repurposing ◽

Respiratory Illness ◽

Human Coronavirus ◽

Anti Hiv

A novel severe acute respiratory syndrome human coronavirus (SARS HCoV) was identified from respiratory illness patients (named SARS-CoV-2 by ICTV) in December 2019 and has recently emerged as a serious threat to world public health.

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Resveratrol Inhibits HCoV-229E and SARS-CoV-2 Coronavirus Replication In Vitro

Viruses ◽

10.3390/v13020354 ◽

2021 ◽

Vol 13 (2) ◽

pp. 354

Author(s):

Sébastien Pasquereau ◽

Zeina Nehme ◽

Sandy Haidar Ahmad ◽

Fadoua Daouad ◽

Jeanne Van Assche ◽

...

Keyword(s):

Drug Repurposing ◽

Effective Concentration ◽

Selectivity Index ◽

Viral Titer ◽

Human Coronavirus ◽

Candidate Drug ◽

Drug Compounds ◽

Low Cytotoxicity ◽

Novel Coronavirus

A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China at the end of 2019 causing a large global outbreak. As treatments are of the utmost importance, drug repurposing embodies a rich and rapid drug discovery landscape, where candidate drug compounds could be identified and optimized. To this end, we tested seven compounds for their ability to reduce replication of human coronavirus (HCoV)-229E, another member of the coronavirus family. Among these seven drugs tested, four of them, namely rapamycin, disulfiram, loperamide and valproic acid, were highly cytotoxic and did not warrant further testing. In contrast, we observed a reduction of the viral titer by 80% with resveratrol (50% effective concentration (EC50) = 4.6 µM) and lopinavir/ritonavir (EC50 = 8.8 µM) and by 60% with chloroquine (EC50 = 5 µM) with very limited cytotoxicity. Among these three drugs, resveratrol was less cytotoxic (cytotoxic concentration 50 (CC50) = 210 µM) than lopinavir/ritonavir (CC50 = 102 µM) and chloroquine (CC50 = 67 µM). Thus, among the seven drugs tested against HCoV-229E, resveratrol demonstrated the optimal antiviral response with low cytotoxicity with a selectivity index (SI) of 45.65. Similarly, among the three drugs with an anti-HCoV-229E activity, namely lopinavir/ritonavir, chloroquine and resveratrol, only the latter showed a reduction of the viral titer on SARS-CoV-2 with reduced cytotoxicity. This opens the door to further evaluation to fight Covid-19.

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Main Protease Inhibitors and Drug Surface Hotspot for the Treatment of COVID-19: Drug Repurposing and Molecular Docking Approach

10.26434/chemrxiv.12118857 ◽

2020 ◽

Author(s):

Mahmudul Hasan ◽

Md Sorwer Alam Parvez ◽

Kazi Faizul Azim ◽

Abdus Shukur Imran ◽

Topu Raihan ◽

...

Keyword(s):

Molecular Docking ◽

Drug Repurposing ◽

Pharmacokinetic Parameters ◽

The Novel ◽

Drug Candidates ◽

Target Drug ◽

Global Pandemic ◽

Main Protease ◽

Docking Approach ◽

Repurposed Drugs

<div>The world is facing an unprecedented global pandemic caused by the novel SARS-CoV-2. In the absence</div><div>of a specific therapeutic agent to treat COVID-19 patients, the present study aimed to virtually screen out</div><div>the effective drug candidates from the approved main protease protein (MPP) inhibitors and their</div><div>derivatives for the treatment of SARS-CoV-2. Here, drug repurposing and molecular docking were</div><div>employed to screen approved MPP inhibitors and their derivatives. The approved MPP inhibitors against</div><div>HIV and HCV were prioritized, whilst hydroxychloroquine, favipiravir, remdesivir, and alpha-ketoamide</div><div>were studied as control. The target drug surface hotspot was also investigated through the molecular</div><div>docking technique. ADME analysis was conducted to understand the pharmacokinetics and drug-likeness</div><div>of the screened MPP inhibitors. The result of this study revealed that Paritaprevir (-10.9 kcal/mol), and its</div><div>analog (CID 131982844)(-16.3 kcal/mol) showed better binding affinity than the approved MPP inhibitor</div><div>compared in this study including favipiravir, remdesivir, and alpha-ketoamide. A comparative study among</div><div>the screened putative MPP inhibitors revealed that amino acids T25, T26, H41, M49, L141, N142, G143,</div><div>C145, H164, M165, E166, D187, R188, and Q189 are at critical positions for becoming the surface hotspot</div><div>in the MPP of SARS-CoV-2. The study also suggested that paritaprevir and its' analog (CID 131982844),</div><div>may be effective against SARS-CoV-2 as these molecules had the common drug-surface hotspots on the</div><div>main protease protein of SARS-CoV-2. Other pharmacokinetic parameters also indicate that paritaprevir</div><div>and its top analog (CID 131982844) will be either similar or better-repurposed drugs than already approved</div><div>MPP inhibitors. </div><div><br></div>

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A Review on Drug Repurposing: A Strategy to Treat Human Coronavirus Disease (COVID-19)

International Journal of TROPICAL DISEASE & Health ◽

10.9734/ijtdh/2020/v41i2130407 ◽

2020 ◽

pp. 42-54

Author(s):

Neetu Bhattacharya ◽

Shashank Kumar Maurya ◽

Sabyasachi Senapati ◽

Amit Bhattacharya

Keyword(s):

Indian Subcontinent ◽

Drug Repurposing ◽

Controlled Clinical Trials ◽

Wuhan City ◽

Human Coronavirus ◽

Plasma Therapy ◽

Mass Immunization ◽

Place Of Origin ◽

Repurposed Drugs ◽

Novel Coronavirus

Novel coronavirus pandemic has created a massive public health emergency causing around 1.85 million deaths world-wide till 5th January, 2021. New SARS (Severe Acute Respiratory Syndrome) coronavirus strain known as SARS-CoV-2 is the causative agent which infected more than 84 million people across the globe. Current epicentre of the pandemic has shifted to Europe and United States and Indian subcontinent from its place of origin-Wuhan City, Hubei province in China. Due to limited availability of vaccines against SARS-CoV-2 or its related β-coronavirus (SARS-CoV or MERS-CoV), mass immunization is currently not possible. Thus, use of curative therapies could be the only choice of intervention. Therefore, rapid treatment of millions of COVID-19 patients in limited time can only be achieved by repurposing pre-approved and existing drugs. Network-based high-throughput computational approach has also predicted several repurposable drugs. Cheaper, less toxic and well tolerated drugs such as antimalarial drugs: Chloroquine (CQ) & Hydroxychloroquine (HCQ); antiviral drugs: Remdesivir, Lopinavir and Ritonavir are among many others that have been proposed for the COVID-19 treatment. Presently limited controlled clinical trials are underway to assess the therapeutic outcome of these repurposed drugs along with novel candidate vaccines and medicines. Beside these, convalescent plasma therapy has also emerged as potential therapeutic approach being tested in several countries. This review focuses on few of the promising repurposed drugs and their outcomes that are presently under evaluation for their safety and efficacy against the coronavirus disease 2019 (COVID-19).

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A Novel Pipeline for Drug Repurposing for Bladder Cancer Based on Patients’ Omics Signatures

Cancers ◽

10.3390/cancers12123519 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3519

Author(s):

Marika Mokou ◽

Vasiliki Lygirou ◽

Ioanna Angelioudaki ◽

Nikolaos Paschalidis ◽

Rafael Stroggilos ◽

...

Keyword(s):

Bladder Cancer ◽

Molecular Subtypes ◽

Drug Repurposing ◽

Colony Growth ◽

Competitive Inhibitor ◽

Connectivity Map ◽

Target Drug ◽

Muscle Invasive ◽

Therapeutic Compounds ◽

Very High

Multi-omics signatures of patients with bladder cancer (BC) can guide the identification of known de-risked therapeutic compounds through drug repurposing, an approach not extensively explored yet. In this study, we target drug repurposing in the context of BC, driven by tissue omics signatures. To identify compounds that can reverse aggressive high-risk Non-Muscle Invasive BC (NMIBC) to less aggressive low-risk molecular subtypes, the next generation Connectivity Map (CMap) was employed using as input previously published proteomics and transcriptomics respective signatures. Among the identified compounds, the ATP-competitive inhibitor of mTOR, WYE-354, showed a consistently very high score for reversing the aggressive BC molecular signatures. WYE-354 impact was assessed in a panel of eight multi-origin BC cell lines and included impaired colony growth and proliferation rate without any impact on apoptosis. Overall, with this study we introduce a promising pipeline for the repurposing of drugs for BC treatment, based on patients’ omics signatures.

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