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1.
Indian Journal of Biochemistry and Biophysics ; 59(9):879-891, 2022.
Article in English | Scopus | ID: covidwho-2030669

ABSTRACT

Drug repurposing is a major approach used by researchers to tackle the COVID-19 pandemic which has been worsened by the current surge of delta variant in many countries. Though drugs like Remdesivir and Hydroxychloroquine have been repurposed, studies prove these drugs have insignificant effect in treatment. So, in this study, we use the already FDA approved database of 1615 drugs to apply semi-flexible and flexible molecular docking methods to calculate the docking scores and identify the best 20 potential inhibitors for our modelled delta variant spike protein RBD. Then, we calculate 2325 1-D and 2-D molecular descriptors and use machine-learning algorithms like K-Nearest Neighbor, Random Forest, Support Vector Machine and ensemble stacking method to build regression-based prediction models. We identify 15 best descriptors for the dataset all of which were found to be inversely correlated with ligand binding. With only these few descriptors, the models performed excellently with an area under curve (AUC) value of 0.952 in Regression Error Characteristic curve for ensemble stacking. Therefore, we comment that these 15 descriptors are the most important features for the binding of inhibitors to the spike protein and hence these should be studied properly in terms of drug repurposing and drug discovery. © 2022, National Institute of Science Communication and Policy Research. All rights reserved.

2.
Stem Cells and COVID-19 ; : 169-227, 2022.
Article in English | Scopus | ID: covidwho-2027798

ABSTRACT

The outbreak of the Coronavirus disease 2019 (COVID-19) caused by the viral pathogen, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rampantly spread across the globe and has been declared a pandemic by the World Health Organization in 2020. COVID-19 has impacted the economy, public health system, and even daily life. Several viral epidemics, mainly SARS-CoV, H1N1, and MERS-CoV, were reported in the past two decades, whereas SARS-CoV-2 is a newly discovered virus from the coronavirus family. In this chapter, we give a brief overview of the structure, etiology, and transmission of the SARS-CoV-2 and move on to describe the clinical manifestations, diagnosis, and current methods adopted for the treatment of COVID-19 patients. An in-depth insight into the role of immunomodulators, repurposed drugs, thromboprophylactics, convalescent plasma, and stem cells as therapeutics is provided. The chapter also focuses on future perspectives and research strategies that are being actively explored for the management and mitigation of COVID-19. The role of the route of administration of therapeutics with pertinence on nasal vaccines is highlighted. Finally, the use of biomaterials and tissue engineering approaches for designing effective interventional strategies is detailed. It is of paramount importance that host-pathogen interactions and pathomechanisms of infections are delineated in order to identify suitable targets for intervention. The attained knowledge may be extended to manage other infectious viral diseases and thereby future pandemics. © 2022 Elsevier Inc. All rights reserved.

3.
Structural Chemistry ; : 1-16, 2022.
Article in English | Academic Search Complete | ID: covidwho-2014356

ABSTRACT

The SARS-CoV-2 proteases Mpro and PLpro are important targets for the development of antivirals against COVID-19. The functional group 1,2,4-thiadiazole has been indicated to inhibit cysteinyl proteases, such as papain and cathepsins. Of note, the 1,2,4-thiadiazole moiety is found in a new class of cephalosporin FDA-approved antibiotics: ceftaroline fosamil, ceftobiprole, and ceftobiprole medocaril. Here we investigated the interaction of these new antibiotics and their main metabolites with the SARS-CoV-2 proteases by molecular docking, molecular dynamics (MD), and density functional theory (DFT) calculations. Our results indicated the PLpro enzyme as a better in silico target for the new antibacterial cephalosporins. The results with ceftaroline fosamil and the dephosphorylate metabolite compounds should be tested as potential inhibitor of PLpro, Mpro, and SARS-CoV-2 replication in vitro. In addition, the data here reported can help in the design of new potential drugs against COVID-19 by exploiting the S atom reactivity in the 1,2,4-thiadiazole moiety. [ FROM AUTHOR] Copyright of Structural Chemistry is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

4.
Struct Chem ; : 1-9, 2022 Jul 26.
Article in English | MEDLINE | ID: covidwho-2014353

ABSTRACT

The novel coronavirus that has affected the whole world is declared a pandemic by the World Health Organization. Since the emergence of this virus, researchers worldwide have searched for potential antivirals against it. Being an RNA virus, it shows a high rate of mutability and variability in its genome. In the present study, all the reported SARS-CoV-2 genomes isolated from diverse regions of the world available in the GISAID database have been considered for phylogenetic analysis. The strain identified at the root is subjected to phylogenetic analysis with genomes of other known human viruses obtained from NCBI for identifying the nearest viral neighbor. Furthermore, the phylogenetic relationship between various human viruses was used to repurpose the known antiviral drugs towards coronavirus using in silico docking approach. The phylogeny reveals the link of the COVID virus with adenovirus. The known drugs against adenovirus are considered in the present study for drug repurposing through molecular docking analysis. The reference inhibitors of the respective targets were also considered in the docking study. The protein targets, namely protease, endoribonuclease, methyltransferase, phosphatase, and spike protein, are considered for screening with the known drug of adenovirus. Ribavirin, known to treat adenoviral infection, shows the best docking score, suggesting its use as a repurposed drug to treat SARS-CoV-2. Furthermore, the potency of the ribavirin drug is analyzed using molecular dynamics studies. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02019-6.

5.
Computers in Biology and Medicine ; : 105992, 2022.
Article in English | ScienceDirect | ID: covidwho-2003986

ABSTRACT

Drug repurposing is an approach to identify new medical indications of approved drugs. This work presents a graph neural network drug repurposing model, which we refer to as GDRnet, to efficiently screen a large database of approved drugs and predict the possible treatment for novel diseases. We pose drug repurposing as a link prediction problem in a multi-layered heterogeneous network with about 1.4 million edges capturing complex interactions between nearly 42,000 nodes representing drugs, diseases, genes, and human anatomies. GDRnet has an encoder–decoder architecture, which is trained in an end-to-end manner to generate scores for drug-disease pairs under test. We demonstrate the efficacy of the proposed model on real datasets as compared to other state-of-the-art baseline methods. For a majority of the diseases, GDRnet ranks the actual treatment drug in the top 15. Furthermore, we apply GDRnet on a coronavirus disease (COVID-19) dataset and show that many drugs from the predicted list are being studied for their efficacy against the disease.

6.
Infect Disord Drug Targets ; 2022 Aug 11.
Article in English | MEDLINE | ID: covidwho-1993669

ABSTRACT

BACKGROUND: COVID-19, caused by SARS-corona virus-2, is a global wide expanded public health risk at a bizarre level. In this current situation, COVID-19 became a serious emerging pandemic. Choosing drug reusing is a crucial step in identifying the new uses of old established drugs. To achieve a significant and healthy way of treatment in COVID patients within a short duration, drug repurposing is a novel method. OBJECTIVE: The present study concentrated on the molecular docking of thalidomide and its analogues and Apremilast against Coronavirus infectious symptoms, evaluated on virus proteins (Spike Protein, 3cl Protease, Nucleocapsids). METHODS: The present study explores the possibility of repurposing thalidomide for the treatment of SARS-COV-2 infection by assessing and confirming with docking affinity scores of thalidomide & its analogues and Apremilast, with spike protein, 3cl protease, and nucleocapsids. RESULTS: From the study results, thalidomide, pomalidomide, lenalidomide, and Apremilast exhibited better binding affinity to N Protein (4KXJ), Protease (4WY3) and Spike Protein (5WRG). In comparison of targets, N Protein - 4KXJ is the best for the four ligands. It is finalized that all four ligands (Thalidomide - -8.6, Pomalidomide - -8.8, Lenalidomide,and - -8.2,and Apremilast - -8.1) have good docking scores with the target N Protein. CONCLUSION: The present study shows confirmation that thalidomide and its analogues and apremilast as a better fit for treating high risk patients of COVID -19 viral infection which are supposed to promote beneficial effects for both respiratory illnesses like COVID-19 symptoms as well as improve the pathological state of condition.

7.
Comb Chem High Throughput Screen ; 2022 Aug 16.
Article in English | MEDLINE | ID: covidwho-1993659

ABSTRACT

BACKGROUND: The SARS-CoV-2 coronavirus (COVID-19) has raised innumerable global concerns, and few effective treatment strategy has yet been permitted by the FDA to lighten the disease burden. SARS-CoV-2 3C-like proteinase (3CLP) is a crucial protease and plays a key role in the viral life cycle, as it controls replication, and thus, it is viewed as a target for drug design. METHOD: In this study, we performed structure-based virtual screening of FDA drugs approved during the period 2015-2019 (total 220 drugs) for interaction with the active site of 3CLP (PDB ID 6LU7) using AutoDock 4.2. We report the top ten drugs that outperform the reported drugs against 3CLP (Elbasvir and Nelfinavir), particularly Cefiderocol having the highest affinity among the compounds tested, with a binding energy of -9.97 kcal/mol. H-bond (LYS102:HZ2-ligand:O49), hydrophobic (ligand-VAL104), and electrostatic (LYS102:NZ-ligand:O50) interactions were observed in cefiderocol-3CLP complex. The docked complex was subjected to a 50 ns molecular dynamics study to check its stability, and stable RMSD and RMSF graphs were observed. RESULT: Accordingly, we suggest cefiderocol might be effective against SARS-CoV-2 and urge that experimental validation to be performed to determine the antiviral efficacy of cefiderocol against SARS-CoV-2. DISCUSSION: Along with these, cefiderocol is effective for the treatment of respiratory tract pathogens and wide range of gram-negative bacteria for whom there are limited therapeutic alternatives. CONCLUSION: The aim of this article was to explore the FDA approved drugs as repurposing study against 3CLP for COVID-19 management.

8.
Advances and Applications in Bioinformatics and Chemistry ; 15:59-77, 2022.
Article in English | ProQuest Central | ID: covidwho-1993622

ABSTRACT

Background: Since the last COVID-19 outbreak, several approaches have been given a try to quickly tackle this global calamity. One of the well-established strategies is the drug repurposing, which consists in finding new therapeutic uses for approved drugs. Following the same paradigm, we report in the present study, an investigation of the potential inhibitory activity of 5-FU and nineteen of its analogues against the SARS-CoV-2 main protease (3CLpro). Material and Methods: Molecular docking calculations were performed to investigate the binding affinity of the ligands within the active site of 3CLpro. The best binding candidates were further considered for molecular dynamics simulations for 100 ns to gain a time-resolved understanding of the behavior of the guest-host complexes. Furthermore, the profile of druggability of the best binding ligands was assessed based on ADMET predictions. Finally, their chemical reactivity was elucidated using different reactivity descriptors, namely the molecular electrostatic potential (MEP), Fukui functions and frontier molecular orbitals. Results and Discussion: From the calculations performed, four candidates (compounds 14, 15, 16 and 18) show promising results with respect to the binding affinity to the target protease, 3CLpro, the therapeutic profile of druggability and safety. These compounds are maintained inside the active site of 3CLpro thanks to a variety of noncovalent interactions, especially hydrogen bonds, involving important amino acids such as GLU166, HIS163, GLY143, ASN142, HIS172, CYS145. Molecular dynamics simulations suggest that the four ligands are well trapped within the active site of the protein over a time gap of 100 ns, ligand 18 being the most retained. Conclusion: In line with the findings reported herein, we recommend that further in-vitro and in-vivo investigations are carried out to shed light on the possible mechanism of pharmacological action of the proposed ligands.

9.
J Control Release ; 2022 Aug 10.
Article in English | MEDLINE | ID: covidwho-1991137

ABSTRACT

Since the recent clinical approval of siRNA-based drugs and COVID-19 mRNA vaccines, the potential of RNA therapeutics for patient healthcare has become widely accepted. Lipid nanoparticles (LNPs) are currently the most advanced nanocarriers for RNA packaging and delivery. Nevertheless, the intracellular delivery efficiency of state-of-the-art LNPs remains relatively low and safety- and immunogenicity concerns with synthetic lipid components persist, altogether rationalizing the exploration of alternative LNP compositions. In addition, there is an interest in exploiting LNP technology for simultaneous encapsulation of small molecule drugs and RNA in a single nanocarrier. Here, we describe how well-known tricyclic cationic amphiphilic drugs (CADs) can be repurposed as both structural and functional components of lipid-based NPs for mRNA formulation, further referred to as CADosomes. We demonstrate that selected CADs, such as tricyclic antidepressants and antihistamines, self-assemble with the widely-used helper lipid DOPE to form cationic lipid vesicles for subsequent mRNA complexation and delivery, without the need for prior lipophilic derivatization. Selected CADosomes enabled efficient mRNA delivery in various in vitro cell models, including easy-to-transfect cancer cells (e.g. human cervical carcinoma HeLa cell line) as well as hard-to-transfect primary cells (e.g. primary bovine corneal epithelial cells), outperforming commercially available cationic liposomes and state-of-the-art LNPs. In addition, using the antidepressant nortriptyline as a model compound, we show that CADs can maintain their pharmacological activity upon CADosome incorporation. Furthermore, in vivo proof-of-concept was obtained, demonstrating CADosome-mediated mRNA delivery in the corneal epithelial cells of rabbit eyes, which could pave the way for future applications in ophthalmology. Based on our results, the co-formulation of CADs, helper lipids and mRNA into lipid-based nanocarriers is proposed as a versatile and straightforward approach for the rational development of drug combination therapies.

10.
Front Public Health ; 10: 902123, 2022.
Article in English | MEDLINE | ID: covidwho-1987598

ABSTRACT

The global spread of the SARS coronavirus 2 (SARS-CoV-2), its manifestation in human hosts as a contagious disease, and its variants have induced a pandemic resulting in the deaths of over 6,000,000 people. Extensive efforts have been devoted to drug research to cure and refrain the spread of COVID-19, but only one drug has received FDA approval yet. Traditional drug discovery is inefficient, costly, and unable to react to pandemic threats. Drug repurposing represents an effective strategy for drug discovery and reduces the time and cost compared to de novo drug discovery. In this study, a generic drug repurposing framework (SperoPredictor) has been developed which systematically integrates the various types of drugs and disease data and takes the advantage of machine learning (Random Forest, Tree Ensemble, and Gradient Boosted Trees) to repurpose potential drug candidates against any disease of interest. Drug and disease data for FDA-approved drugs (n = 2,865), containing four drug features and three disease features, were collected from chemical and biological databases and integrated with the form of drug-disease association tables. The resulting dataset was split into 70% for training, 15% for testing, and the remaining 15% for validation. The testing and validation accuracies of the models were 99.3% for Random Forest and 99.03% for Tree Ensemble. In practice, SperoPredictor identified 25 potential drug candidates against 6 human host-target proteomes identified from a systematic review of journals. Literature-based validation indicated 12 of 25 predicted drugs (48%) have been already used for COVID-19 followed by molecular docking and re-docking which indicated 4 of 13 drugs (30%) as potential candidates against COVID-19 to be pre-clinically and clinically validated. Finally, SperoPredictor results illustrated the ability of the platform to be rapidly deployed to repurpose the drugs as a rapid response to emergent situations (like COVID-19 and other pandemics).


Subject(s)
COVID-19 , Drug Repositioning , COVID-19/drug therapy , Drug Repositioning/methods , Humans , Machine Learning , Molecular Docking Simulation , SARS-CoV-2
11.
J King Saud Univ Sci ; : 102277, 2022 Aug 10.
Article in English | MEDLINE | ID: covidwho-1977532

ABSTRACT

Human ezrin protein interacts with SARS-CoV S endodomain and restrict the virus fusion, entry, and their early events of infection. In general, their binding strength and their structural stability determines their entry into the host cells. However, the binding affinity of these two endodomains with the ezrin protein has been elusive due to a paucity of knowledge on the 3D structure. This study modelled the endodomains of both SARS-CoV-1 and SARS-CoV-2 and then docked these models with human ezrin protein. This study establishes that the modelled endodomains of both SARS-CoV-1 and SARS-Cov-2 consisted of three disulphide bridges for self-stabilization. Protein-protein docking listed four salt bridges with a higher buried surface area between ezrin-SARS-CoV-1 endodomain compared to that of ezrin-SARS-CoV-2 with six salt bridges with lower buried surface area. Molecular simulation of the ezrin-SARS-CoV-1 endodomain showed better structural stability with lower Root Mean Square Deviation score compared to that of ezrin-SARS-CoV-2 endodomain due to the substitution of Alanine with Cysteine residue. Protein-ligand docking studies confirmed better ezrin-drug interaction for quercetin, minocycline, calcifediol, calcitriol, selamectin, Ivermectin and ergocalciferol. However, protein-ligand simulation confirmed strong drug-protein interaction during simulation for all the above-listed drugs except for ergocalciferol which could not establish its interaction with the protein during simulation. Strong drug binding within the active site pocket therefore restricts the interaction of viral endodomain and simultaneously stabilizes the ezrin protein. Furthermore, the higher stability between the ezrin after their interaction with the drug moiety could restrict the virus fusion and the infection. This study provides a basis for further development of these drug molecules to clinical trials aiming to identify potential drug molecules which can treat covid-19 infection.

12.
J Biomol Struct Dyn ; : 1-12, 2022 Jul 31.
Article in English | MEDLINE | ID: covidwho-1967740

ABSTRACT

This study proposes a novel model for integration of SARS-CoV-2 into host cell via endocytosis as a possible alternative to the prevailing direct fusion model. It is known that the SARS-CoV-2 spike protein undergoes proteolytic cleavage at S1-S2 cleavage site and the cleaved S2 domain is primed by the activated serine protease domain (SPD) of humanTMPRSS2 to become S2'. The activated SPD of TMPRSS2 is formed after it is cleaved by autocatalysis from the membrane bound non-catalytic ectodomain (hNECD) comprising of LDLRA CLASS-I repeat and a SRCR domain. It is known that the SRCR domains as well as LDLRA repeat harboring proteins mediate endocytosis of viruses and certain ligands. Based on this, we put forward a hypothesis that the exposed hNECD binds to the S2' as both are at an interaction proximity soon after S2 is processed by the SPD and this interaction may lead to the endocytosis of virus. Based on this hypothesis we have modelled the hNECD structure, followed by docking studies with the known 3D structure of S2'. The interaction interface of hNECD with S2' was further used for virtual screening of FDA-approved drug molecules and Indian medicinal plant-based compounds. We also mapped the known mutations of concern and mutations of interest on interaction interface of S2' and found that none of the known mutations map onto the interaction interface. This indicates that targeting the interaction between the hNECD of TMPRSS2 and S2' may serve as an attractive therapeutic target.Communicated by Ramaswamy H. Sarma.

13.
Curr Res Microb Sci ; 3: 100158, 2022.
Article in English | MEDLINE | ID: covidwho-1966467

ABSTRACT

Sublineages of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) Omicron variants continue to amass mutations in the spike (S) glycoprotein, which leads to immune evasion and rapid spread of the virus across the human population. Here we demonstrate the susceptibility of the Omicron variant BA.1 (B.1.1.529.1) to four repurposable drugs, Methylene blue (MB), Mycophenolic acid (MPA), Posaconazole (POS), and Niclosamide (Niclo) in post-exposure treatments of primary human airway cell cultures. MB, MPA, POS, and Niclo are known to block infection of human nasal and bronchial airway epithelial explant cultures (HAEEC) with the Wuhan strain, and four variants of concern (VoC), Alpha (B.1.1.7), Beta (B.1.351), Gamma (B.1.1.28), Delta (B.1.617.2) (Weiss et al., 2021, Murer et al., 2022). Our results here not only reinforce the broad anti-coronavirus effects of MB, MPA, POS and Niclo, but also demonstrate that the Omicron variant BA.1 (B.1.1.529.1) sheds infectious virus from HAEEC over at least 15 d, and maintains both intracellular and extracellular viral genomic RNA without overt toxicity, suggesting viral persistence. The data emphasize the potential of repurposable drugs against COVID-19.

14.
Journal of Environmental Pathology, Toxicology and Oncology ; 41(3):45-64, 2022.
Article in English | Scopus | ID: covidwho-1963173

ABSTRACT

On December 2019, the world faced a new pandemic caused by a novel type of coronavirus, namely severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This disease is named as “coronavirus disease 2019 (COVID-19).” This RNA virus infected millions of people around the world causing millions of deaths. It takes approx-imately 8–10 years to develop a new drug and it seems hard to have a specific pharmaceutical agent against COVID-19. So far, there is only one drug that has applied for registration. The drugs used in clinics against COVID-19 were approved for malaria, human immunodeficiency syndrome (HIV), influenza A and B, and other viral diseases. All these drugs for COVID-19 treatment are being applied according to “drug repurposing (drug repositioning)” strategy. However, they could cause some severe adverse effects on susceptible populations. In some cases, patients can survive after dis-ease. However, the adverse effects of these drugs may lead to morbidity and mortality later. In this review, drugs used against COVID-19 in clinics, their mechanisms of action and possible adverse effects on susceptible populations will be discussed. © 2022 by Begell House, Inc. www.begellhouse.com.

15.
Int J Mol Sci ; 23(13)2022 Jun 21.
Article in English | MEDLINE | ID: covidwho-1963997

ABSTRACT

Treatment options for Coronavirus Disease 2019 (COVID-19) remain limited, and the option of repurposing approved drugs with promising medicinal properties is of increasing interest in therapeutic approaches to COVID-19. Using computational approaches, we examined griseofulvin and its derivatives against four key anti-SARS-CoV-2 targets: main protease, RdRp, spike protein receptor-binding domain (RBD), and human host angiotensin-converting enzyme 2 (ACE2). Molecular docking analysis revealed that griseofulvin (CID 441140) has the highest docking score (-6.8 kcal/mol) with main protease of SARS-CoV-2. Moreover, griseofulvin derivative M9 (CID 144564153) proved the most potent inhibitor with -9.49 kcal/mol, followed by A3 (CID 46844082) with -8.44 kcal/mol against M protease and ACE2, respectively. Additionally, H bond analysis revealed that compound A3 formed the highest number of hydrogen bonds, indicating the strongest inhibitory efficacy against ACE2. Further, molecular dynamics (MD) simulation analysis revealed that griseofulvin and these derivatives are structurally stable. These findings suggest that griseofulvin and its derivatives may be considered when designing future therapeutic options for SARS-CoV-2 infection.


Subject(s)
COVID-19 , Angiotensin-Converting Enzyme 2 , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Griseofulvin/pharmacology , Griseofulvin/therapeutic use , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
16.
J Biomol Struct Dyn ; : 1-23, 2022 Jul 25.
Article in English | MEDLINE | ID: covidwho-1956485

ABSTRACT

The use of US FDA-approved drugs is preferred due to the need for lower costs and less time. In in silico medicine, repurposing is a quick and accurate way to screen US FDA-approved medications to find a therapeutic option for COVID-19 infection. Dual inhibitors possess dual inhibitory activity, which may be due to the inhibition of two different enzymes, and are considered better than combination therapy from the developmental and clinical perspectives. In this study, a molecular docking simulation was performed to identify the interactions of antiviral drugs with the critical residues in the binding site of the main SARS-CoV-2 protease, spike glycoprotein, and papain-like protease receptors compared to the angiotensin-converting enzyme-related carboxypeptidase (ACE2) receptor of host cells. Each of the receptors was docked with 70 US FDA-approved antiviral drugs using AutoDock Vina. A molecular dynamics (MD) simulation study was also used for 100 ns to confirm the stability behaviour of the ligand receptor complexes. Among the drugs that had the strongest interaction with the SARS-CoV-2 main protease, spike glycoprotein and papain-like protease receptors, and host cell ACE2 receptors, Simeprevir, Maraviroc and Saquinavir had dual inhibitory effects. The MD simulation study confirmed the stability of the strongest interactions between the antiviral drugs and the main protease, ACE2, spike glycoprotein, and papain-like protease receptors to 100 ns. However the results of MMPBSA analysis showed that the bond between Saquinavir and the ACE2 receptor was weak. Simeprevir and Maraviroc drugs had acceptable binding energies with dual receptors, especially the Simeprevir.Communicated by Ramaswamy H. Sarma.

17.
Int J Biol Sci ; 18(12): 4768-4780, 2022.
Article in English | MEDLINE | ID: covidwho-1954698

ABSTRACT

The pandemic of COVID-19 is the biggest public health crisis in 21st Century. Besides the acute symptoms after infection, patients and society are also being challenged by the long-term health complications associated with COVID-19, commonly known as long COVID. While health professionals work hard to find proper treatments, large amount of knowledge has been accumulated in recent years. In order to deal with long COVID efficiently, it is important for people to keep up with current progresses and take proactive actions on long COVID. For this purpose, this review will first introduce the general background of long COVID, and then discuss its risk factors, diagnostic indicators and management strategies. This review will serve as a useful resource for people to understand and prepare for long COVID that will be with us in the foreseeable future.


Subject(s)
COVID-19 , COVID-19/complications , Health Personnel , Humans , Pandemics , SARS-CoV-2
18.
Biology (Basel) ; 11(3)2022 Feb 26.
Article in English | MEDLINE | ID: covidwho-1952946

ABSTRACT

NF-κB is a central mediator of inflammation, response to DNA damage and oxidative stress. As a result of its central role in so many important cellular processes, NF-κB dysregulation has been implicated in the pathology of important human diseases. NF-κB activation causes inappropriate inflammatory responses in diseases including rheumatoid arthritis (RA) and multiple sclerosis (MS). Thus, modulation of NF-κB signaling is being widely investigated as an approach to treat chronic inflammatory diseases, autoimmunity and cancer. The emergence of COVID-19 in late 2019, the subsequent pandemic and the huge clinical burden of patients with life-threatening SARS-CoV-2 pneumonia led to a massive scramble to repurpose existing medicines to treat lung inflammation in a wide range of healthcare systems. These efforts continue and have proven to be controversial. Drug repurposing strategies are a promising alternative to de novo drug development, as they minimize drug development timelines and reduce the risk of failure due to unexpected side effects. Different experimental approaches have been applied to identify existing medicines which inhibit NF-κB that could be repurposed as anti-inflammatory drugs.

19.
Inform Med Unlocked ; 31: 100979, 2022.
Article in English | MEDLINE | ID: covidwho-1945263

ABSTRACT

The SARS-CoV-2 is one of the most infectious and deadly coronaviruses, which has gripped the world, causing the COVID-19 pandemic. Despite the numerous studies being conducted on this virus, many uncertainties are with the disease. This is exacerbated by the speedy mutations acquired by the viral strain, which enables the disease to present itself differently in different people, introducing new factors of uncertainty. This study aims at the identification of regulatory pathways across two cell lines, namely, the peripheral blood mononuclear cell line (PBMC) and the normal human bronchial epithelial (NHBE) cell line. Both the above-mentioned cell lines were considered because they support viral replication. Furthermore, the NHBE cell line captures vital changes in the lungs, which are the main organs affected by the COVID-19 patients, and the PBMC cell line is closely linked to the body's immune system. RNA-Seq analysis, differential gene expression and gene set enrichment analysis for pathway identification were followed. Pathway analysis throws light upon the various systems affected in the body due to the COVID-19. Gene regulatory networks associated with the significant pathways were also designed. These networks aid in identifying various gene targets, along with their interactions. Studying the functionality of the pathways and the gene interactions associated with them, aided by long COVID studies, will provide immense clarity about the current COVID-19 scenario. In the long term, this will help in the design of therapeutic approaches against the SARS-CoV-2 and can also contribute to drug repurposing studies. Ultimately, this study identifies and analyses the relationship of various undiscovered or lesser explored pathways in the human body to the SARS-CoV-2 and establish a clearer picture of the association to help streamline further studies and approaches.

20.
Comput Biol Med ; 147: 105709, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1944685

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the contagious coronavirus disease 2019 (COVID-19) which was first identified in Wuhan, China, in December 2019. Around the world, many researchers focused their research on identifying inhibitors against the druggable SARS-CoV-2 targets. The reported genomic mutations have a direct effect on the receptor-binding domain (RBD), which interacts with host angiotensin-converting enzyme 2 (ACE-2) for viral cell entry. These mutations, some of which are variants of concern (VOC), lead to increased morbidity and mortality rates. The newest variants including B.1.617.2 (Delta), AY.1 (Delta plus), and C.37 (Lambda) were considered in this study. Thus, an exhaustive structure-based virtual screening of a ligand library (in which FDA approved drugs are also present) using the drug-likeness screening, molecular docking, ADMET profiling was performed followed by molecular dynamics (MD) simulation, and Molecular Mechanics-Poisson Boltzmann Surface Area (MM-PBSA) calculation to identify compounds or drugs can be repurposed for inhibiting the wild type, Delta, Delta plus and Lambda variants of RBD of the spike protein. Based on the virtual screening steps, two FDA approved drugs, Atovaquone (atv) and Praziquantel (prz), were selected and repurposed as the best candidates of SARS-CoV-2 RBD inhibitors. Molecular docking results display that both atv and prz contribute in different interaction with binding site residues (Gln493, Asn501 and Gly502 in the hydrogen bond formation, Phe490 and Tyr505 in the π- π stacking and Tyr449, Ser494, and Phe497 in the vdW interactions) in the wild type, Delta, Delta plus and Lambda variants of RBD of the spike protein. MD simulations revealed that among the eight studied complexes, the wild type-atv and Delta-prz complexes have the most structural stability over the simulation time. Furthermore, MM-PBSA calculation showed that in the atv containing complexes, highest binding affinity is related to the wild type-atv complex and in the prz containing complexes, it is related to the Delta-prz complex. The validation of docking results was done by comparing with experimental data (heparin in complex with wild type and Delta variants). Also, comparison of the obtained results with the result of simulation of the k22 with the studied proteins showed that atv and prz are suitable inhibitors for these proteins, especially wild type t and Delta variant, respectively. Thus, we found that atv and prz are the best candidate for inhibition of wild type and Delta variant of the spike protein. Also, atv can be an appropriate inhibitor for the Lambda variant. Obtained in silico results may help the development of new anti-COVID-19 drugs.


Subject(s)
COVID-19 , SARS-CoV-2 , Adipates , COVID-19/drug therapy , COVID-19/genetics , Drug Repositioning/methods , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Mutation/genetics , Peptidyl-Dipeptidase A/chemistry , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Succinates
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