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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An evidence-based systematic review on emerging therapeutic and preventive strategies to treat novel coronavirus (SARS-CoV-2) during an outbreak scenario

Journal of Basic and Clinical Physiology and Pharmacology ◽

10.1515/jbcpp-2020-0113 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Anupama M. Gudadappanavar ◽

Jyoti Benni

Keyword(s):

Antiviral Drug ◽

Drug Repurposing ◽

Respiratory Illness ◽

World Health ◽

Recombinant Vaccines ◽

Subunit Vaccines ◽

Coronavirus Infection ◽

Novel Coronavirus ◽

Health Organization ◽

Full Length Genome

AbstractA novel coronavirus infection coronavirus disease 2019 (COVID-19) emerged from Wuhan, Hubei Province of China, in December 2019 caused by SARS-CoV-2 is believed to be originated from bats in the local wet markets. Later, animal to human and human-to-human transmission of the virus began and resulting in widespread respiratory illness worldwide to around more than 180 countries. The World Health Organization declared this disease as a pandemic in March 2020. There is no clinically approved antiviral drug or vaccine available to be used against COVID-19. Nevertheless, few broad-spectrum antiviral drugs have been studied against COVID-19 in clinical trials with clinical recovery. In the current review, we summarize the morphology and pathogenesis of COVID-19 infection. A strong rational groundwork was made keeping the focus on current development of therapeutic agents and vaccines for SARS-CoV-2. Among the proposed therapeutic regimen, hydroxychloroquine, chloroquine, remdisevir, azithromycin, toclizumab and cromostat mesylate have shown promising results, and limited benefit was seen with lopinavir–ritonavir treatment in hospitalized adult patients with severe COVID-19. Early development of SARS-CoV-2 vaccine started based on the full-length genome analysis of severe acute respiratory syndrome coronavirus. Several subunit vaccines, peptides, nucleic acids, plant-derived, recombinant vaccines are under pipeline. This article concludes and highlights ongoing advances in drug repurposing, therapeutics and vaccines to counter COVID-19, which collectively could enable efforts to halt the pandemic virus infection.

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Translational and Clinical Pharmacology Considerations in Drug Repurposing for X-linked Adrenoleukodystrophy-A Rare Peroxisomal Disorder

10.22541/au.162610374.45880274/v1 ◽

2021 ◽

Author(s):

Julianne Tieu ◽

Siddhee Sahasrabudhe ◽

Paul Orchard ◽

James Cloyd ◽

Reena Kartha

Keyword(s):

Drug Target ◽

Drug Targets ◽

Drug Repurposing ◽

Pharmacokinetics And Pharmacodynamics ◽

Drug Candidates ◽

Target Patient Population ◽

Site Of Action ◽

Repurposed Drugs ◽

Gait Disturbances ◽

Spastic Quadriparesis

X-linked adrenoleukodystrophy (X-ALD) is an inherited, neurodegenerative rare disease that can result in devastating symptoms of blindness, gait disturbances, and spastic quadriparesis due to progressive demyelination. Typically, the disease progresses rapidly, causing death within the first decade of life. With limited treatments available, efforts to determine an effective therapy that can alter disease progression or mitigate symptoms have been undertaken for many years, particularly through drug repurposing. Repurposing has generally been guided through clinical experience and small trials. At this time, none of the drug candidates have been approved for use, which may be due, in part, to the lack of pharmacokinetic/pharmacodynamic (PK/PD) information on the repurposed medications in the target patient population. Greater consideration for the disease pathophysiology, drug pharmacology, and potential drug-target interactions, specifically at the site of action, would improve drug repurposing and facilitate development. Although there is a good understanding of X-ALD pathophysiology, the absence of information on drug targets, pharmacokinetics, and pharmacodynamics hinders the repurposing of drugs for this condition. Incorporating advanced translational and clinical pharmacological approaches in preclinical studies and early stages clinical trials will improve the success of repurposed drugs for X-ALD as well as other rare diseases.

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Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication

Nature Communications ◽

10.1038/s41467-020-18096-2 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 19

Author(s):

Wayne Vuong ◽

Muhammad Bashir Khan ◽

Conrad Fischer ◽

Elena Arutyunova ◽

Tess Lamer ◽

...

Keyword(s):

Drug Target ◽

Covalent Modification ◽

Human Coronavirus ◽

Feline Infectious Peritonitis ◽

Drug Candidates ◽

Main Protease ◽

Coronavirus Infection ◽

Reversible Formation ◽

Nanomolar Range ◽

Feline Coronavirus

Abstract The main protease, Mpro (or 3CLpro) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide. Feline infectious peritonitis, a fatal coronavirus infection in cats, was successfully treated previously with a prodrug GC376, a dipeptide-based protease inhibitor. Here, we show the prodrug and its parent GC373, are effective inhibitors of the Mpro from both SARS-CoV and SARS-CoV-2 with IC50 values in the nanomolar range. Crystal structures of SARS-CoV-2 Mpro with these inhibitors have a covalent modification of the nucleophilic Cys145. NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal. GC373 and GC376 are potent inhibitors of SARS-CoV-2 replication in cell culture. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals. The work here lays the framework for their use in human trials for the treatment of 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.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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Virtual Screening of Some Antivirals That Can Be Repurposed As Potential Effective Drugs against SARS-CoV-2

10.26434/chemrxiv.12923684 ◽

2020 ◽

Author(s):

Mohammad Rejaur Rahman ◽

Anik Banik ◽

Ishtiak Malique Chowdhury ◽

Emran Sajib ◽

Sanchita Sarkar

Keyword(s):

Rna Binding ◽

Viral Infections ◽

Toxicity Testing ◽

Drug Repurposing ◽

Drug Candidates ◽

Docking Method ◽

Speed Up ◽

Coronavirus Infection ◽

Effective Drugs ◽

Drug Similarity

<p>SARS-CoV-2 has triggered a big epidemic among people around the world and it is the newest in the sequence to be prevalent among other infectious diseases. Drug repurposing concept has been utilized effectively for numerous viral infections. Considering the situation and the urgency, the idea of drug repurposing for coronavirus infection (COVID-19) is also being studied. Screening with molecular docking method for 29 antiviral drugs was performed against SARSCoV-2 primary protease proteins (MPP), spike ecto-domain, spike receptor binding domain, Nsp9 RNA binding protein,and HR2 domain. Among these drugs, Indinavir, Sorivudine, Cidofovir and Darunavir show minimum docking scores with all key proteins in terms of least binding energy. For ADME (Absorption, Distribution, Metabolism, and Excretion) analysis, the top 4 drug candidates were further used to examine their drug profiles for suitability against SARS-CoV-2. The toxicity testing of top drug candidates showed no significant carcinogenic, mutagenic or skin irritating impacts. Indinavir may possess some complexity to heart. In addition, the drug similarity prediction revealed several approved structural analogues such as Telbivudine, Tenofovir, Amprenavir, Fosamprenavir etc which also could be used to treat viral infections. The study may speed up the findings of therapeutics against SARS-CoV-2. <br></p>

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Virtual Screening of Some Antivirals That Can Be Repurposed As Potential Effective Drugs against SARS-CoV-2

10.26434/chemrxiv.12923684.v1 ◽

2020 ◽

Author(s):

Mohammad Rejaur Rahman ◽

Anik Banik ◽

Ishtiak Malique Chowdhury ◽

Emran Sajib ◽

Sanchita Sarkar

Keyword(s):

Rna Binding ◽

Viral Infections ◽

Toxicity Testing ◽

Drug Repurposing ◽

Drug Candidates ◽

Docking Method ◽

Speed Up ◽

Coronavirus Infection ◽

Effective Drugs ◽

Drug Similarity

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The Anatomy of the SARS-CoV-2 Biomedical Literature: Introducing the CovidX Network Algorithm for Drug Repurposing Recommendation

Journal of Medical Internet Research ◽

10.2196/21169 ◽

2020 ◽

Vol 22 (8) ◽

pp. e21169

Author(s):

Lyndsey Elaine Gates ◽

Ahmed Abdeen Hamed

Keyword(s):

Clinical Trials ◽

Language Processing ◽

Antiviral Drug ◽

Drug Repurposing ◽

Biomedical Literature ◽

Drug Candidates ◽

Fast Development ◽

Drug Knowledge ◽

Biomedical Publications ◽

Multiple Drugs

Background Driven by the COVID-19 pandemic and the dire need to discover an antiviral drug, we explored the landscape of the SARS-CoV-2 biomedical publications to identify potential treatments. Objective The aims of this study are to identify off-label drugs that may have benefits for the coronavirus disease pandemic, present a novel ranking algorithm called CovidX to recommend existing drugs for potential repurposing, and validate the literature-based outcome with drug knowledge available in clinical trials. Methods To achieve such objectives, we applied natural language processing techniques to identify drugs and linked entities (eg, disease, gene, protein, chemical compounds). When such entities are linked, they form a map that can be further explored using network science tools. The CovidX algorithm was based upon a notion that we called “diversity.” A diversity score for a given drug was calculated by measuring how “diverse” a drug is calculated using various biological entities (regardless of the cardinality of actual instances in each category). The algorithm validates the ranking and awards those drugs that are currently being investigated in open clinical trials. The rationale behind the open clinical trial is to provide a validating mechanism of the PubMed results. This ensures providing up to date evidence of the fast development of this disease. Results From the analyzed biomedical literature, the algorithm identified 30 possible drug candidates for repurposing, ranked them accordingly, and validated the ranking outcomes against evidence from clinical trials. The top 10 candidates according to our algorithm are hydroxychloroquine, azithromycin, chloroquine, ritonavir, losartan, remdesivir, favipiravir, methylprednisolone, rapamycin, and tilorone dihydrochloride. Conclusions The ranking shows both consistency and promise in identifying drugs that can be repurposed. We believe, however, the full treatment to be a multifaceted, adjuvant approach where multiple drugs may need to be taken at the same time.

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Computational guided approach for drug repurposing against SARS-CoV-2

Future Virology ◽

10.2217/fvl-2020-0403 ◽

2021 ◽

Author(s):

Jigisha Anand ◽

Tanmay Ghildiyal ◽

Aakanksha Madhwal ◽

Rishabh Bhatt ◽

Devvret Verma ◽

...

Keyword(s):

Drug Targets ◽

De Novo ◽

Drug Repositioning ◽

Drug Repurposing ◽

Computational Docking ◽

Drug Candidates ◽

Docking Tool ◽

Inhibitory Potential ◽

Approved Drugs ◽

Tract Infections

Background: In the current SARS-CoV-2 outbreak, drug repositioning emerges as a promising approach to develop efficient therapeutics in comparison to de novo drug development. The present investigation screened 130 US FDA-approved drugs including hypertension, cardiovascular diseases, respiratory tract infections (RTI), antibiotics and antiviral drugs for their inhibitory potential against SARS-CoV-2. Materials & methods: The molecular drug targets against SARS-CoV-2 proteins were determined by the iGEMDOCK computational docking tool. The protein homology models were generated through SWISS Model workspace. The pharmacokinetics of all the ligands was determined by ADMET analysis. Results: The study identified 15 potent drugs exhibiting significant inhibitory potential against SARS-CoV-2. Conclusion: Our investigation has identified possible repurposed drug candidates to improve the current modus operandi of the treatment given to COVID-19 patients.

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Elucidation on the Physicochemical Properties of Potential and Clinically Approved Antiviral Drugs: A Search for Effective Therapies against SARS-CoV-2 Infection

Journal of Pure and Applied Microbiology ◽

10.22207/jpam.14.spl1.41 ◽

2020 ◽

Vol 14 (suppl 1) ◽

pp. 1025-1034

Author(s):

Derick Erl P. Sumalapao

Keyword(s):

Antiviral Activity ◽

Physicochemical Properties ◽

Vaccine Development ◽

Heavy Atom ◽

Antiviral Drug ◽

Principal Component ◽

Antiviral Drugs ◽

Medical Emergency ◽

Drug Candidates ◽

Additional Information

COVID-19 has been confirmed in millions of individuals worldwide, rendering it a global medical emergency. In the absence of vaccines and the unavailability of effective drugs for the SARS-CoV-2 infection, vaccine development is being continuously explored and several antiviral compounds and immunotherapies are currently being investigated. Given the high similarity in genetic identity between SARS-CoV and SARS-CoV-2, the present investigation identified the interaction between the physicochemical properties and the antiviral activity of different potential and clinically approved antiviral drugs against SARS-CoV using hierarchically weighted principal component analysis. Representative drugs from the classes of neuraminidase inhibitors, reverse transcriptase inhibitors, protease inhibitors, nucleoside analogues, and other compounds with potential antiviral activity were examined. The pharmacologic classification and the biological activity of the different antiviral drugs were described using indices, namely, rotatable bond count, molecular weight, heavy atom count, and molecular complexity (92.32% contribution rate). The physicochemical properties and inhibitory action against SARS-CoV-2 of lopinavir, chloroquine, ivermectin, and ciclesonide validated the adequacy of the current computational approach. The findings of the present study provide additional information, although further investigation is warranted to identify potential targets and establish exact mechanisms, in the emergent search and design of antiviral drug candidates and their subsequent synthesis as effective therapies for COVID-19.

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