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1.
Thromb J ; 18: 22, 2020.
Article in English | MEDLINE | ID: covidwho-1793931

ABSTRACT

BACKGROUND: Hospitals in the Middle East Gulf region have experienced an influx of COVID-19 patients to their medical wards and intensive care units. The hypercoagulability of these patients has been widely reported on a global scale. However, many of the experimental treatments used to manage the various complications of COVID-19 have not been widely studied in this context. The effect of the current treatment protocols on patients' diagnostic and prognostic biomarkers may thus impact the validity of the algorithms adopted. CASE PRESENTATION: In this case series, we report four cases of venous thromboembolism and 1 case of arterial thrombotic event, in patients treated with standard or intensified prophylactic doses of unfractionated heparin or low molecular weight heparin at our institution. Tocilizumab has been utilized as an add-on therapy to the standard of care to treat patients with SARS-CoV-2 associated acute respiratory distress syndrome, in order to dampen the hyperinflammatory response. It is imperative to be aware that this drug may be masking the inflammatory markers (e.g. IL6, CRP, fibrinogen, and ferritin), without reducing the risk of thrombotic events in this population, creating instead a façade of an improved prognostic outcome. However, the D-dimer levels remained prognostically reliable in these cases, as they were not affected by the drug and continued to be at the highest level until event occurrence. CONCLUSIONS: In the setting of tocilizumab therapy, traditional prognostic markers of worsening infection and inflammation, and thus potential risk of acute thrombosis, should be weighed carefully as they may not be reliable for prognosis and may create a façade of an improved prognostic outcome insteasd. Additionally, the fact that thrombotic events continued to be observed despite decrease in inflammatory markers and the proactive anticoagulative approach adopted, raises more questions about the coagulative mechanisms at play in COVID-19, and the appropriate management strategy.

2.
Am J Epidemiol ; 190(8): 1452-1456, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1585169

ABSTRACT

The coronavirus disease 2019 pandemic, which was caused by the severe acute respiratory syndrome coronavirus 2, has led to an unprecedented effort to generate real-world evidence on the safety and effectiveness of various treatments. A growing number of observational studies in which the effects of certain drugs were evaluated have been conducted, including several in which researchers assessed whether hydroxychloroquine improved outcomes in infected individuals and whether renin-angiotensin-aldosterone system inhibitors have detrimental effects. In the present article, we review and illustrate how immortal time bias and selection bias were present in several of these studies. Understanding these biases and how they can be avoided may prove important for future observational studies assessing the effectiveness and safety of potentially promising drugs during the coronavirus 19 pandemic.


Subject(s)
COVID-19/drug therapy , Cohort Studies , Drug Evaluation/methods , Randomized Controlled Trials as Topic , Bias , Humans , Research Design , SARS-CoV-2
3.
Antimicrob Agents Chemother ; 65(8): e0049121, 2021 07 16.
Article in English | MEDLINE | ID: covidwho-1486471

ABSTRACT

In the present report, we describe two small molecules with broad-spectrum antiviral activity. These drugs block the formation of the nodosome. The studies were prompted by the observation that infection of human fetal brain cells with Zika virus (ZIKV) induces the expression of nucleotide-binding oligomerization domain-containing protein 2 (NOD2), a host factor that was found to promote ZIKV replication and spread. A drug that targets NOD2 was shown to have potent broad-spectrum antiviral activity against other flaviviruses, alphaviruses, enteroviruses, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). Another drug that inhibits receptor-interacting serine/threonine protein kinase 2 (RIPK2), which functions downstream of NOD2, also decreased the replication of these pathogenic RNA viruses. The antiviral effect of this drug was particularly potent against enteroviruses. The broad-spectrum action of nodosome-targeting drugs is mediated in part by the enhancement of the interferon response. Together, these results suggest that further preclinical investigation of nodosome inhibitors as potential broad-spectrum antivirals is warranted.


Subject(s)
Arboviruses , COVID-19 , Zika Virus Infection , Zika Virus , Antiviral Agents/pharmacology , Humans , SARS-CoV-2 , Virus Replication
4.
Dev Neurosci ; 43(3-4): 143-158, 2021.
Article in English | MEDLINE | ID: covidwho-1472320

ABSTRACT

The mechanistic target of rapamycin (mTOR) is a kinase at the center of an evolutionarily conserved signaling pathway that orchestrates cell growth and metabolism. mTOR responds to an array of intra- and extracellular stimuli and in turn controls multiple cellular anabolic and catabolic processes. Aberrant mTOR activity is associated with numerous diseases, with particularly profound impact on the nervous system. mTOR is found in two protein complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), which are governed by different upstream regulators and have distinct cellular actions. Mutations in genes encoding for mTOR regulators result in a collection of neurodevelopmental disorders known as mTORopathies. While these disorders can affect multiple organs, neuropsychiatric conditions such as epilepsy, intellectual disability, and autism spectrum disorder have a major impact on quality of life. The neuropsychiatric aspects of mTORopathies have been particularly challenging to treat in a clinical setting. Current therapeutic approaches center on rapamycin and its analogs, drugs that are administered systemically to inhibit mTOR activity. While these drugs show some clinical efficacy, adverse side effects, incomplete suppression of mTOR targets, and lack of specificity for mTORC1 or mTORC2 may limit their utility. An increased understanding of the neurobiology of mTOR and the underlying molecular, cellular, and circuit mechanisms of mTOR-related disorders will facilitate the development of improved therapeutics. Animal models of mTORopathies have helped unravel the consequences of mTOR pathway mutations in specific brain cell types and developmental stages, revealing an array of disease-related phenotypes. In this review, we discuss current progress and potential future directions for the therapeutic treatment of mTORopathies with a focus on findings from genetic mouse models.


Subject(s)
Autism Spectrum Disorder , Animals , Humans , Mechanistic Target of Rapamycin Complex 1/metabolism , Mechanistic Target of Rapamycin Complex 2/metabolism , Mice , Quality of Life , Signal Transduction
5.
Inform Med Unlocked ; 24: 100617, 2021.
Article in English | MEDLINE | ID: covidwho-1409424

ABSTRACT

The high pathogenic nature of the Middle East Respiratory coronavirus (MER) and the associated high fatality rate demands an urgent attention from researchers. Because there is currently no approved drug for the management of the disease, research efforts have been intensified towards the discovery of a potent drug for the treatment of the disease. Papain Like protease (PLpro) is one of the key proteins involved in the viral replication. We therefore docked forty-six compounds already characterized from Azadirachta indica, Xylopia aethipica and Allium cepa against MERS-CoV-PLpro. The molecular docking analysis was performed with AutoDock 1.5.6 and compounds which exhibit more negative free energy of binding, and low inhibition constant (Ki) with the protein (MERS-CoV-PLpro) were considered potent. The physicochemical and pharmacokinetic properties of the compounds were predicted using the Swissadme web server. Twenty-two of the compounds showed inhibition potential similar to dexamethasone and remdesvir, which had binding affinity of -6.8 and -6.3 kcal/mol respectively. The binding affinity of the compounds ranged between -3.4 kcal/mol and -7.7 kcal/mol whereas; hydroxychloroquine had a binding affinity of -4.5 kcal/mol. Among all the compounds, nimbanal and verbenone showed drug likeliness, they did not violate the Lipinski rule neither were they inhibitors of drug-metabolizing enzymes. Both nimbanal and verbenone were further post-scored with MM/GBSA and the binding free energy of nimbanal (-25.51 kcal/mol) was comparable to that of dexamethasone (-25.46 kcal/mol). The RMSD, RMSF, torsional angle, and other analysis following simulation further substantiate the efficacy of nimbanal as an effective drug candidate. In conclusion, our study showed that nimbanal is a more promising therapeutic agent and could be a lead for the discovery of a new drug that may be useful in the management of severe respiratory coronavirus syndrome.

6.
Evid Based Complement Alternat Med ; 2020: 4932572, 2020.
Article in English | MEDLINE | ID: covidwho-1394264

ABSTRACT

COVID-19 is a disease caused by severe acute respiratory syndrome coronavirus 2. Presently, there is no effective treatment for COVID-19. As part of the worldwide efforts to find efficient therapies and preventions, it has been reported the crystalline structure of the SARS-CoV-2 main protease Mpro (also called 3CLpro) bound to a synthetic inhibitor, which represents a major druggable target. The druggability of Mpro could be used for discovering drugs to treat COVID-19. A multilevel computational study was carried out to evaluate the potential antiviral properties of the components of the medicinal herb Uncaria tomentosa (Cat's claw), focusing on the inhibition of Mpro. The in silico approach starts with protein-ligand docking of 26 Cat's claw key components, followed by ligand pathway calculations, molecular dynamics simulations, and MM-GBSA calculation of the free energy of binding for the best docked candidates. The structural bioinformatics approaches led to identification of three bioactive compounds of Uncaria tomentosa (speciophylline, cadambine, and proanthocyanidin B2) with potential therapeutic effects by strong interaction with 3CLpro. Additionally, in silico drug-likeness indices for these components were calculated and showed good predicted therapeutic profiles of these phytochemicals. Our findings suggest the potential effectiveness of Cat's claw as complementary and/or alternative medicine for COVID-19 treatment.

7.
J Biomol Struct Dyn ; 39(15): 5756-5767, 2021 09.
Article in English | MEDLINE | ID: covidwho-1390290

ABSTRACT

Herein, the DrugBank database which contains 10,036 approved and investigational drugs was explored deeply for potential drugs that target SARS-CoV-2 main protease (Mpro). Filtration process of the database was conducted using three levels of accuracy for molecular docking calculations. The top 35 drugs with docking scores > -11.0 kcal/mol were then subjected to 10 ns molecular dynamics (MD) simulations followed by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. The results showed that DB02388 and Cobicistat (DB09065) exhibited potential binding affinities towards Mpro over 100 ns MD simulations, with binding energy values of -49.67 and -46.60 kcal/mol, respectively. Binding energy and structural analyses demonstrated the higher stability of DB02388 over Cobicistat. The potency of DB02388 and Cobicistat is attributed to their abilities to form several hydrogen bonds with the essential amino acids inside the active site of Mpro. Compared to DB02388 and Cobicistat, Darunavir showed a much lower binding affinity of -34.83 kcal/mol. The present study highlights the potentiality of DB02388 and Cobicistat as anti-COVID-19 drugs for clinical trials. Communicated by Ramaswamy H. Sarma.


Subject(s)
COVID-19 , Protease Inhibitors , Drug Repositioning , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , SARS-CoV-2
9.
Ann Rheum Dis ; 80(10): 1317-1321, 2021 10.
Article in English | MEDLINE | ID: covidwho-1388467

ABSTRACT

BACKGROUND: The registration trials of messenger RNA (mRNA) vaccines against SARS-CoV-2 did not address patients with inflammatory rheumatic diseases (IRD). OBJECTIVE: To assess the humoral response after two doses of mRNA vaccine against SARS-CoV-2, in patients with IRD treated with immunomodulating drugs and the impact on IRD activity. METHODS: Consecutive patients treated at the rheumatology institute, who received their first SARS-CoV-2 (Pfizer) vaccine, were recruited to the study, at their routine visit. They were reassessed 4-6 weeks after receiving the second dose of vaccine, and blood samples were obtained for serology. IRD activity assessment and the vaccine side effects were documented during both visits. IgG antibodies (Abs) against SARS-CoV-2 were detected using the SARS-CoV-2 IgG II Quant (Abbott) assay. RESULTS: Two hundred and sixty-four patients with stable disease, (mean(SD) age 57.6 (13.18) years, disease duration 11.06 (7.42) years), were recruited. The immunomodulatory therapy was not modified before or after the vaccination. After the second vaccination, 227 patients (86%) mounted IgG Ab against SARS-CoV-2 (mean (SD) 5830.8 (8937) AU/mL) and 37 patients (14%) did not, 22/37 were treated with B cell-depleting agents. The reported side effects of the vaccine were minor. The rheumatic disease remained stable in all patients. CONCLUSIONS: The vast majority of patients with IRD developed a significant humoral response following the administration of the second dose of the Pfizer mRNA vaccine against SARS-CoV-2 virus. Only minor side effects were reported and no apparent impact on IRD activity was noted.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunocompromised Host/immunology , Immunogenicity, Vaccine/immunology , Rheumatic Diseases/immunology , Adult , Aged , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antirheumatic Agents , Female , Humans , Male , Middle Aged , SARS-CoV-2
10.
FASEB J ; 35(6): e21651, 2021 06.
Article in English | MEDLINE | ID: covidwho-1388031

ABSTRACT

The SARS-CoV-2 pandemic imposed a large burden on health and society. Therapeutics targeting different components and processes of the viral infection replication cycle are being investigated, particularly to repurpose already approved drugs. Spike protein is an important target for both vaccines and therapeutics. Insights into the mechanisms of spike-ACE2 binding and cell fusion could support the identification of compounds with inhibitory effects. Here, we demonstrate that the integrity of disulfide bonds within the receptor-binding domain (RBD) plays an important role in the membrane fusion process although their disruption does not prevent binding of spike protein to ACE2. Several reducing agents and thiol-reactive compounds are able to inhibit viral entry. N-acetyl cysteine amide, L-ascorbic acid, JTT-705, and auranofin prevented syncytia formation, viral entry into cells, and infection in a mouse model, supporting disulfides of the RBD as a therapeutically relevant target.


Subject(s)
Acetylcysteine/analogs & derivatives , Amides/pharmacology , Ascorbic Acid/pharmacology , Auranofin/pharmacology , COVID-19 , Disulfides/metabolism , Esters/pharmacology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Sulfhydryl Compounds/pharmacology , Virus Internalization/drug effects , Acetylcysteine/pharmacology , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/pathology , HEK293 Cells , Humans
13.
Sci Bull (Beijing) ; 66(9): 925-936, 2021 May 15.
Article in English | MEDLINE | ID: covidwho-1386590

ABSTRACT

The SARS-CoV-2 infection is spreading rapidly worldwide. Efficacious antiviral therapeutics against SARS-CoV-2 is urgently needed. Here, we discovered that protoporphyrin IX (PpIX) and verteporfin, two Food and Drug Administration (FDA)-approved drugs, completely inhibited the cytopathic effect produced by SARS-CoV-2 infection at 1.25 µmol/L and 0.31 µmol/L, respectively, and their EC50 values of reduction of viral RNA were at nanomolar concentrations. The selectivity indices of PpIX and verteporfin were 952.74 and 368.93, respectively, suggesting a broad margin of safety. Importantly, PpIX and verteporfin prevented SARS-CoV-2 infection in mice adenovirally transduced with human angiotensin-converting enzyme 2 (ACE2). The compounds, sharing a porphyrin ring structure, were shown to bind viral receptor ACE2 and interfere with the interaction between ACE2 and the receptor-binding domain of viral S protein. Our study suggests that PpIX and verteporfin are potent antiviral agents against SARS-CoV-2 infection and sheds new light on developing novel chemoprophylaxis and chemotherapy against SARS-CoV-2.

14.
Adv Protein Chem Struct Biol ; 124: 275-309, 2021.
Article in English | MEDLINE | ID: covidwho-1375869

ABSTRACT

The discovery and development of a new drug is a complex, time consuming and costly process that typically takes over 10 years and costs around 1 billion dollars from bench to market. This scenario makes the discovery of novel drugs targeting neglected tropical diseases (NTDs), which afflict in particular people in low-income countries, prohibitive. Despite the intensive use of High-Throughput Screening (HTS) in the past decades, the speed with which new drugs come to the market has remained constant, generating doubts about the efficacy of this approach. Here we review a few of the yeast-based high-throughput approaches that can work synergistically with parasite-based, in vitro, or in silico methods to identify and optimize novel antiparasitic compounds. These yeast-based methods range from HTP screens to identify novel hits against promising parasite kinase targets to the identification of potential antiparasitic kinase inhibitors extracted from databases of yeast chemical genetic screens.


Subject(s)
Drug Discovery , Neglected Diseases , Protein Kinase Inhibitors , Protein Kinases , Saccharomyces cerevisiae , Drug Evaluation, Preclinical , Humans , Neglected Diseases/drug therapy , Neglected Diseases/enzymology , Neglected Diseases/genetics , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Protein Kinases/genetics , Protein Kinases/metabolism , Saccharomyces cerevisiae/enzymology , Saccharomyces cerevisiae/genetics
15.
Brief Bioinform ; 22(2): 1476-1498, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1352121

ABSTRACT

Coronavirus disease 2019 (COVID-19), an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a global pandemic by the World Health Organization, and the situation worsens daily, associated with acute increases in case fatality rates. The main protease (Mpro) enzyme produced by SARS-CoV-2 was recently demonstrated to be responsible for not only viral reproduction but also impeding host immune responses. The element selenium (Se) plays a vital role in immune functions, both directly and indirectly. Thus, we hypothesised that Se-containing heterocyclic compounds might curb the activity of SARS-CoV-2 Mpro. We performed a molecular docking analysis and found that several of the selected selenocompounds showed potential binding affinities for SARS-CoV-2 Mpro, especially ethaselen (49), which exhibited a docking score of -6.7 kcal/mol compared with the -6.5 kcal/mol score for GC376 (positive control). Drug-likeness calculations suggested that these compounds are biologically active and possess the characteristics of ideal drug candidates. Based on the binding affinity and drug-likeness results, we selected the 16 most effective selenocompounds as potential anti-COVID-19 drug candidates. We also validated the structural integrity and stability of the drug candidate through molecular dynamics simulation. Using further in vitro and in vivo experiments, we believe that the targeted compound identified in this study (ethaselen) could pave the way for the development of prospective drugs to combat SARS-CoV-2 infections and trigger specific host immune responses.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Heterocyclic Compounds/pharmacology , Protease Inhibitors/pharmacology , Selenium/analysis , Antiviral Agents/chemistry , Computational Biology , Computer Simulation , Coronavirus 3C Proteases/chemistry , Heterocyclic Compounds/chemistry , Humans , Ligands , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/chemistry , Protein Structure, Tertiary , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Reproducibility of Results , Sulfonic Acids
16.
Clin Ther ; 43(4): 711-719, 2021 04.
Article in English | MEDLINE | ID: covidwho-1349418

ABSTRACT

PURPOSE: In patients with primary hyperparathyroidism (PHPT) and severe hypercalcemia, parathyroidectomy remains the only curative therapy. During the coronavirus disease 2019 (COVID-19) pandemic, when many hospital visits are suspended and surgeries cannot be performed, the management of these patients represents a challenging clinical situation. This article presents a literature review and discussion of the pharmacologic management of PHPT and severe hypercalcemia, which can be used as a temporary measure during the COVID-19 pandemic until parathyroidectomy can be performed safely. METHODS: This narrative review was conducted by searching literature on the PubMed, Medline, and Google Scholar databases using the terms primary hyperparathyroidism, hypercalcemia, cinacalcet, bisphosphonates, denosumab, vitamin D, raloxifene, hormone replacement therapy, coronavirus, and COVID-19. FINDINGS: Appropriate monitoring and remote medical follow-up of these patients are essential until the resolution of the pandemic. Cinacalcet is the drug of choice for controlling hypercalcemia, whereas bisphosphonate or denosumab is the drug for improving bone mineral density. Combined therapy with cinacalcet and bisphosphonates or cinacalcet and denosumab should be considered when the effects on serum calcium and bone mineral density are simultaneously desired. IMPLICATIONS: Medical management of PHPT and severe hypercalcemia presents a reasonable alternative for parathyroid surgery during the COVID-19 outbreak and should be instituted until the pandemic ends and surgery can be performed safely.


Subject(s)
COVID-19 , Hypercalcemia/drug therapy , Hyperparathyroidism, Primary/drug therapy , Bone Density/drug effects , Calcium/blood , Cinacalcet/administration & dosage , Diphosphonates/therapeutic use , Humans , Middle Aged , Parathyroidectomy , Raloxifene Hydrochloride/therapeutic use , Vitamin D/pharmacology
17.
Front Mol Biosci ; 8: 671263, 2021.
Article in English | MEDLINE | ID: covidwho-1344278

ABSTRACT

SARS-CoV-2 belongs to the family of enveloped, single-strand RNA viruses known as Betacoronavirus in Coronaviridae, first reported late 2019 in China. It has since been circulating world-wide, causing the COVID-19 epidemic with high infectivity and fatality rates. As of the beginning of April 2021, pandemic SARS-CoV-2 has infected more than 130 million people and led to more than 2.84 million deaths. Given the severity of the epidemic, scientists from academia and industry are rushing to identify antiviral strategies to combat the disease. There are several strategies in antiviral drugs for coronaviruses including empirical testing of known antiviral drugs, large-scale phenotypic screening of compound libraries and target-based drug discovery. To date, an increasing number of drugs have been shown to have anti-coronavirus activities in vitro and in vivo, but only remdesivir and several neutralizing antibodies have been approved by the US FDA for treating COVID-19. However, remdesivir's clinical effects are controversial and new antiviral drugs are still urgently needed. We will discuss the current status of the drug discovery efforts against COVID-19 and potential future directions. With the ever-increasing movability of human population and globalization of world economy, emerging and reemerging viral infectious diseases seriously threaten public health. Particularly the past and ongoing outbreaks of coronaviruses cause respiratory, enteric, hepatic and neurological diseases in infected animals and human (Woo et al., 2009). The human coronavirus (HCoV) strains (HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1) usually cause common cold with mild, self-limiting upper respiratory tract infections. By contrast, the emergence of three deadly human betacoronaviruses, middle east respiratory syndrome coronavirus (MERS) (Zaki et al., 2012), severe acute respiratory syndrome coronavirus (SARS-CoV) (Lee et al., 2003), the SARS-CoV-2 (Jin et al., 2020a) highlight the need to identify new treatment strategies for viral infections. SARS-CoV-2 is the etiological agent of COVID-19 disease named by World Health Organization (WHO) (Zhu N. et al., 2020). This disease manifests as either an asymptomatic infection or a mild to severe pneumonia. This pandemic disease causes extent morbidity and mortality in the whole world, especially regions out of China. Similar to SARS and MERS, the SARS CoV-2 genome encodes four structural proteins, sixteen non-structural proteins (nsp) and accessory proteins. The structural proteins include spike (S), envelope (E), membrane (M), nucleoprotein (N). The spike glycoprotein directly recognizes and engages cellular receptors during viral entry. The four non-structural proteins including papain-like protease (PLpro), 3-chymotrypsin-like protease (3CLpro), helicase, and RNA-dependent RNA polymerase (RdRp) are key enzymes involved in viral transcription and replication. The spike and the four key enzymes were considered attractive targets to develop antiviral agents (Zumla et al., 2016). The catalytic sites of the four enzymes of SARS-CoV2 share high similarities with SARS CoV and MERS in genomic sequences (Morse et al., 2020). Besides, the structures of the key drug-binding pockets are highly conserved among the three coronaviruses (Morse et al., 2020). Therefore, it follows naturally that existing anti-SARS-CoV and anti-MERS drugs targeting these enzymes can be repurposed for SARS-CoV-2. Based on previous studies in SARS-CoV and MERS-CoV, it is anticipated a number of therapeutics can be used to control or prevent emerging infectious disease COVID-19 (Li and de Clercq, 2020; Wang et al., 2020c; Ita, 2021), these include small-molecule drugs, peptides, and monoclonal antibodies. Given the urgency of the SARS-CoV-2 outbreak, here we discuss the discovery and development of new therapeutics for SARS-CoV-2 infection based on the strategies from which the new drugs are derived.

18.
Curr Comput Aided Drug Des ; 17(3): 469-479, 2021.
Article in English | MEDLINE | ID: covidwho-1344218

ABSTRACT

BACKGROUND: 2019-nCoVis, a novel coronavirus was isolated and identified in 2019 in the city of Wuhan, China. On February 17, 2020 and according to the World Health Organization, 71, 429 confirmed cases worldwide were identified, among them 2162 new cases were recorded in the last 24 hours. One month later, the confirmed cases jumped to 179111, with 11525 new cases in the last 24 hours, with 7426 total deaths. No drug or vaccine is present at the moment for human and animal coronavirus. METHODS: The inhibition of 3CL hydrolase enzyme provides a promising therapeutic principle for developing treatments against CoViD-19. The 3CLpro (Mpro) is known for involving in counteracting the host innate immune response. RESULTS: This work presents the inhibitory effect of some natural compounds against 3CL hydrolase enzyme, and explains the main interactions in inhibitor-enzyme complex. Molecular docking study was carried out using Autodock Vina. By screening several molecules, we identified three candidate agents that inhibit the main protease of coronavirus. Hispidin, lepidine E, and folic acid are bound tightly in the enzyme, therefore strong hydrogen bonds have been formed (1.69-1.80Å) with the active site residues. CONCLUSION: This study provides a possible therapeutic strategy for CoViD-19.


Subject(s)
COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Drug Design , Folic Acid/pharmacology , Molecular Docking Simulation , Pyrones/pharmacology , SARS-CoV-2/drug effects , Viral Protease Inhibitors/pharmacology , Binding Sites , COVID-19/virology , Catalytic Domain , Computer-Aided Design , Coronavirus 3C Proteases/metabolism , Folic Acid/chemistry , Hydrogen Bonding , Molecular Structure , Protein Binding , Pyrones/chemistry , SARS-CoV-2/enzymology , Structure-Activity Relationship , Viral Protease Inhibitors/chemistry
19.
Brief Bioinform ; 22(2): 1430-1441, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1343652

ABSTRACT

The COVID-19 disease led to an unprecedented health emergency, still ongoing worldwide. Given the lack of a vaccine or a clear therapeutic strategy to counteract the infection as well as its secondary effects, there is currently a pressing need to generate new insights into the SARS-CoV-2 induced host response. Biomedical data can help to investigate new aspects of the COVID-19 pathogenesis, but source heterogeneity represents a major drawback and limitation. In this work, we applied data integration methods to develop a Unified Knowledge Space (UKS) and used it to identify a new set of genes associated with SARS-CoV-2 host response, both in vitro and in vivo. Functional analysis of these genes reveals possible long-term systemic effects of the infection, such as vascular remodelling and fibrosis. Finally, we identified a set of potentially relevant drugs targeting proteins involved in multiple steps of the host response to the virus.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/genetics , COVID-19/physiopathology , COVID-19/virology , Genes, Viral , Humans , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Transcriptome
20.
Brief Bioinform ; 22(2): 1254-1266, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1343630

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is accountable for the cause of coronavirus disease (COVID-19) that causes a major threat to humanity. As the spread of the virus is probably getting out of control on every day, the epidemic is now crossing the most dreadful phase. Idiopathic pulmonary fibrosis (IPF) is a risk factor for COVID-19 as patients with long-term lung injuries are more likely to suffer in the severity of the infection. Transcriptomic analyses of SARS-CoV-2 infection and IPF patients in lung epithelium cell datasets were selected to identify the synergistic effect of SARS-CoV-2 to IPF patients. Common genes were identified to find shared pathways and drug targets for IPF patients with COVID-19 infections. Using several enterprising Bioinformatics tools, protein-protein interactions (PPIs) network was designed. Hub genes and essential modules were detected based on the PPIs network. TF-genes and miRNA interaction with common differentially expressed genes and the activity of TFs are also identified. Functional analysis was performed using gene ontology terms and Kyoto Encyclopedia of Genes and Genomes pathway and found some shared associations that may cause the increased mortality of IPF patients for the SARS-CoV-2 infections. Drug molecules for the IPF were also suggested for the SARS-CoV-2 infections.


Subject(s)
COVID-19/complications , Idiopathic Pulmonary Fibrosis/complications , SARS-CoV-2/genetics , COVID-19/genetics , COVID-19/virology , Datasets as Topic , Epithelial Cells/virology , Gene Ontology , Genes, Viral , Humans , Lung/cytology , Lung/virology , Transcriptome
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