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1.
J Antibiot (Tokyo) ; 75(6): 321-332, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1878523

ABSTRACT

Staphylococcus aureus is one of the most dangerous pathogens commonly associated with high levels of morbidity and mortality. Sortase A is considered as a promising molecular target for the development of antistaphylococcal agents. Using hybrid virtual screening approach and FRET analysis, we have identified five compounds able to decrease the activity of sortase A by more than 50% at the concentration of 200 µM. The most promising compound was 2-(2-amino-3-chloro-benzoylamino)-benzoic acid which was able to inhibit S. aureus sortase A at the IC50 value of 59.7 µM. This compound was selective toward sortase A compared to other four cysteine proteases - cathepsin L, cathepsin B, rhodesain, and the SARS-CoV2 main protease. Microscale thermophoresis experiments confirmed that this compound bound sortase A with KD value of 189 µM. Antibacterial and antibiofilm assays also confirmed high specificity of the hit compound against two standard and three wild-type, S. aureus hospital infection isolates. The effect of the compound on biofilms produced by two S. aureus ATCC strains was also observed suggesting that the compound reduced biofilm formation by changing the biofilm structure and thickness.


Subject(s)
COVID-19 , Staphylococcal Infections , Aminoacyltransferases , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/metabolism , Biofilms , Cysteine Endopeptidases , Humans , Microbial Sensitivity Tests , RNA, Viral/pharmacology , SARS-CoV-2 , Staphylococcus aureus
2.
J Med Chem ; 65(11): 7818-7832, 2022 Jun 09.
Article in English | MEDLINE | ID: covidwho-1873394

ABSTRACT

The worldwide impact of the ongoing COVID-19 pandemic on public health has made imperative the discovery and development of direct-acting antivirals aimed at targeting viral and/or host targets. SARS-CoV-2 3C-like protease (3CLpro) has emerged as a validated target for the discovery of SARS-CoV-2 therapeutics because of the pivotal role it plays in viral replication. We describe herein the structure-guided design of highly potent inhibitors of SARS-CoV-2 3CLpro that incorporate in their structure novel spirocyclic design elements aimed at optimizing potency by accessing new chemical space. Inhibitors of both SARS-CoV-2 3CLpro and MERS-CoV 3CLpro that exhibit nM potency and high safety indices have been identified. The mechanism of action of the inhibitors and the structural determinants associated with binding were established using high-resolution cocrystal structures.


Subject(s)
COVID-19 , Hepatitis C, Chronic , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Coronavirus 3C Proteases , Cysteine Endopeptidases/metabolism , Humans , Pandemics , Peptide Hydrolases , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , SARS-CoV-2
3.
Comput Biol Med ; 146: 105668, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1867012

ABSTRACT

Benzalacetophenones, precursors of flavonoids are aromatic ketones and enones and possess the immunostimulant as well as antiviral activities. Thus, benzalacetophenones were screened against the COVID-19 that could be lethal in patients with compromised immunity. We considered ChEBI recorded benzalacetophenone derivative(s) and evaluated their activity against 3C-like protease (3CLpro), papain-like protease (PLpro), and spike protein of SARS-Cov-2 to elucidate their possible role as antiviral agents. The probable targets for each compound were retrieved from DIGEP-Pred at 0.5 pharmacological activity and all the modulated proteins were enriched to identify the probably regulated pathways, biological processes, cellular components, and molecular functions. In addition, molecular docking was performed using AutoDock 4 and the best-identified hits were subjected to all-atom molecular dynamics simulation and binding energy calculations using molecular mechanics Poisson-Boltzmann surface area (MMPBSA). The compound 4-hydroxycordoin showed the highest druglikeness score and regulated nine proteins of which five were down-regulated and four were upregulated. Similarly, enrichment analysis identified the modulation of multiple pathways concerned with the immune system as well as pathways related to infectious and non-infectious diseases. Likewise, 3'-(3-methyl-2-butenyl)-4'-O-ß-d-glucopyranosyl-4,2'-dihydroxychalcone with 3CLpro, 4-hydroxycordoin with PLpro and mallotophilippen D with spike protein receptor-binding domain showed highest binding affinity, revealed stable interactions during the simulation, and scored binding free energy of -26.09 kcal/mol, -16.28 kcal/mol, and -39.2 kcal/mol, respectively. Predicted anti-SARS-CoV-2 activities of the benzalacetophenones reflected the requirement of wet lab studies to develop novel antiviral candidates.


Subject(s)
COVID-19 , Chalcone , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases , Cysteine Endopeptidases/chemistry , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/chemistry , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
4.
Biophys Chem ; 287: 106829, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1850725

ABSTRACT

The viral main protease (Mpro) from a novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a key enzyme essential for viral replication and has become an attractive target for antiviral drug development. The Mpro forms a functional dimer and exhibits a pH-dependent enzyme activity and dimerization. Here, we report a molecular dynamics (MD) investigation to gain insights into the structural stability of the enzyme dimer at neutral and acidic pH. Our data shows larger changes in structure of the protein with the acidic pH than that with the neutral pH. Structural analysis of MD trajectories reveals a substantial increase in intersubunit separation, the loss of domain contacts, binding free energy and interaction energy of the dimer which implies the protein instability and tendency of dimer dissociation at acidic pH. The loss in the interaction energy is mainly driven by electrostatic interactions. We have identified the intersubunit hydrogen-bonding residues involved in the decreased dimer stability. These findings may be helpful for rational drug design and target evaluation against COVID-19.


Subject(s)
COVID-19 , Coronavirus 3C Proteases , Antiviral Agents/chemistry , Cysteine Endopeptidases/chemistry , Humans , Hydrogen-Ion Concentration , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptide Hydrolases/metabolism , Protease Inhibitors , SARS-CoV-2
5.
Bioorg Chem ; 125: 105850, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1819433

ABSTRACT

Nucleoside precursors and nucleoside analogs occupy an important place in the treatment of viral respiratory pathologies, especially during the current COVID-19 pandemic. From this perspective, the present study has been designed to explore and evaluate the synthesis and spectral characterisation of 5́-O-(lauroyl) thymidine analogs 2-6 with different aliphatic and aromatic groups through comprehensive in vitro antimicrobial screening, cytotoxicity assessment, physicochemical aspects, molecular docking and molecular dynamics analysis, along with pharmacokinetic prediction. A unimolar one-step lauroylation of thymidine under controlled conditions furnished the 5́-O-(lauroyl) thymidine and indicated the selectivity at C-5́ position and the development of thymidine based potential antimicrobial analogs, which were further converted into four newer 3́-O-(acyl)-5́-O-(lauroyl) thymidine analogs in reasonably good yields. The chemical structures of the newly synthesised analogs were ascertained by analysing their physicochemical, elemental, and spectroscopic data. In vitro antimicrobial tests against five bacteria and two fungi, along with the prediction of activity spectra for substances (PASS), indicated promising antibacterial functionality for these thymidine analogs compared to antifungal activity. In support of this observation, molecular docking experiments have been performed against the main protease of SARS-CoV-2, and significant binding affinities and non-bonding interactions were observed against the main protease (6LU7, 6Y84 and 7BQY), considering hydroxychloroquine (HCQ) as standard. Moreover, the 100 ns molecular dynamics simulation process was performed to monitor the behaviour of the complex structure formed by the main protease under in silico physiological conditions to examine its stability over time, and this revealed a stable conformation and binding pattern in a stimulating environment of thymidine analogs. Cytotoxicity determination confirmed that compounds were found less toxic. Pharmacokinetic predictions were investigated to evaluate their absorption, distribution, metabolism and toxic properties, and the combination of pharmacokinetic and drug-likeness predictions has shown promising results in silico. The POM analysis shows the presence of an antiviral (O1δ-, O2δ-) pharmacophore site. Overall, the current study should be of great help in the development of thymidine-based, novel, multiple drug-resistant antimicrobial and COVID-19 drugs.


Subject(s)
COVID-19 , SARS-CoV-2 , Anti-Bacterial Agents , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases , Cysteine Endopeptidases/metabolism , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Protease Inhibitors/chemistry , Thymidine/pharmacology , Viral Nonstructural Proteins/metabolism
6.
Braz J Biol ; 84: e250667, 2022.
Article in English | MEDLINE | ID: covidwho-1817550

ABSTRACT

Nigella sativa is known for the safety profile, containing a wealth of useful antiviral compounds. The main protease (Mpro, 3CLpro) of severe acute respiratory syndrome 2 (SARS-CoV-2) is being considered as one of the most attractive viral target, processing the polyproteins during viral pathogenesis and replication. In the current investigation we analyzed the potency of active component, thymoquinone (TQ) of Nigella sativa against SARS-CoV-2 Mpro. The structures of TQ and Mpro was retrieved from PubChem (CID10281) and Protein Data Bank (PDB ID 6MO3) respectively. The Mpro and TQ were docked and the complex was subjected to molecular dynamic (MD) simulations for a period 50ns. Protein folding effect was analyzed using radius of gyration (Rg) while stability and flexibility was measured, using root means square deviations (RMSD) and root means square fluctuation (RMSF) respectively. The simulation results shows that TQ is exhibiting good binding activity against SARS-CoV-2 Mpro, interacting many residues, present in the active site (His41, Cys145) and also the Glu166, facilitating the pocket shape. Further, experimental approaches are needed to validate the role of TQ against virus infection. The TQ is interfering with pocket maintaining residues as well as active site of virus Mpro which may be used as a potential inhibitor against SARS-CoV-2 for better management of COVID-19.


Subject(s)
COVID-19 , Nigella sativa , Benzoquinones , COVID-19/drug therapy , Coronavirus 3C Proteases , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Nigella sativa/metabolism , SARS-CoV-2 , Viral Proteins/chemistry , Viral Proteins/metabolism
7.
Commun Biol ; 5(1): 391, 2022 04 27.
Article in English | MEDLINE | ID: covidwho-1815611

ABSTRACT

Protease inhibitors are among the most powerful antiviral drugs. However, for SARS-CoV-2 only a small number of protease inhibitors have been identified thus far and there is still a great need for assays that efficiently report protease activity and inhibition in living cells. Here, we engineer a safe VSV-based system to report both gain- and loss-of-function of coronavirus main protease (Mpro/3CLpro/Nsp5) activity in living cells. We use SARS-CoV-2 3CLpro in this system to confirm susceptibility to known inhibitors (boceprevir, GC376, PF-00835231, and PF-07321332/nirmatrelvir) and reevaluate other reported inhibitors (baicalein, ebselen, carmofur, ethacridine, ivermectin, masitinib, darunavir, and atazanavir). Moreover, we show that the system can be adapted to report both the function and the chemical inhibition of proteases from different coronavirus species as well as from distantly related viruses. Together with the fact that live cell assays also reflect compound permeability and toxicity, we anticipate that this system will be useful for both identification and optimization of additional coronavirus protease inhibitors.


Subject(s)
COVID-19 , Cysteine Endopeptidases , Humans , Indoles , Lactams , Leucine , Nitriles , Peptide Hydrolases , Proline , Protease Inhibitors/pharmacology , Pyrrolidinones , SARS-CoV-2 , Viral Proteins/chemistry
8.
Virol Sin ; 37(3): 437-444, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1815255

ABSTRACT

The coronavirus 3C-like (3CL) protease, a cysteine protease, plays an important role in viral infection and immune escape. However, there is still a lack of effective tools for determining the cleavage sites of the 3CL protease. This study systematically investigated the diversity of the cleavage sites of the coronavirus 3CL protease on the viral polyprotein, and found that the cleavage motif were highly conserved for viruses in the genera of Alphacoronavirus, Betacoronavirus and Gammacoronavirus. Strong residue preferences were observed at the neighboring positions of the cleavage sites. A random forest (RF) model was built to predict the cleavage sites of the coronavirus 3CL protease based on the representation of residues in cleavage motifs by amino acid indexes, and the model achieved an AUC of 0.96 in cross-validations. The RF model was further tested on an independent test dataset which were composed of cleavage sites on 99 proteins from multiple coronavirus hosts. It achieved an AUC of 0.95 and predicted correctly 80% of the cleavage sites. Then, 1,352 human proteins were predicted to be cleaved by the 3CL protease by the RF model. These proteins were enriched in several GO terms related to the cytoskeleton, such as the microtubule, actin and tubulin. Finally, a webserver named 3CLP was built to predict the cleavage sites of the coronavirus 3CL protease based on the RF model. Overall, the study provides an effective tool for identifying cleavage sites of the 3CL protease and provides insights into the molecular mechanism underlying the pathogenicity of coronaviruses.


Subject(s)
Coronavirus Infections , Coronavirus , Algorithms , Coronavirus/metabolism , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/genetics , Cysteine Endopeptidases/metabolism , Humans , Machine Learning , Peptide Hydrolases/metabolism , Protease Inhibitors , Viral Proteins/metabolism
9.
Comput Biol Med ; 146: 105572, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1814281

ABSTRACT

BACKGROUND: The SARS-CoV-2 main protease (Mpro) is an attractive target in the COVID-19 drug development process. It catalyzes the polyprotein's translation from viral RNA and specifies a particular cleavage site. Due to the absence of identical cleavage specificity in human cell proteases, targeting Mpro with chemical compounds can obstruct the replication of the virus. METHODS: To explore the potential binding mechanisms of 1,2,3-triazole scaffolds in comparison to co-crystallized inhibitors 11a and 11b towards Mpro, we herein utilized molecular dynamics and enhanced sampling simulation studies. RESULTS AND CONCLUSION: All the 1,2,3-triazole scaffolds interacted with catalytic residues (Cys145 and His41) and binding pocket residues of Mpro involving Met165, Glu166, Ser144, Gln189, His163, and Met49. Furthermore, the adequate binding free energy and potential mean force of the topmost compound 3h was comparable to the experimental inhibitors 11a and 11b of Mpro. Overall, the current analysis could be beneficial in developing the SARS-CoV-2 Mpro potential inhibitors.


Subject(s)
COVID-19 , Molecular Dynamics Simulation , Benchmarking , COVID-19/drug therapy , Coronavirus 3C Proteases , Cysteine Endopeptidases/chemistry , Humans , Molecular Docking Simulation , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , SARS-CoV-2 , Triazoles , Viral Nonstructural Proteins/chemistry
10.
Virology ; 571: 12-20, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1799672

ABSTRACT

An epidemic owing to Norovirus (NoV) has recently been occurring worldwide. Severe cases of NoV can lead to patient death, resulting in significant public health problems. In the early stages of infection, antagonizing the production of host interferon (IFN) is an important strategy for viruses to establish infection. However, the relationship between NoV and interferon and its mechanism remains unclear. In this study, the 3C-like protease encoded by NoV was found to effectively suppress Sendai virus (SEV)-mediated IFN-ß production by cleaving the NF-κB essential modulator (NEMO). Glutamine 205 is the site of NoV3CLpro-mediated cleavage of NEMO and this cleavage suppresses the ability of NEMO to activate downstream IFN production. These findings demonstrate that NoV3CLpro-induced cleavage limits NEMO to the activation of type I IFN signaling. In summary, our findings indicate that NoV3CLpro is a new interferon antagonist, and enhances our understanding of the escape of innate immunity mediated by NoV3CLpro.


Subject(s)
Norovirus , Peptide Hydrolases , Antiviral Agents , Cysteine Endopeptidases , Humans , Interferon-beta/genetics , Interferons/genetics , Norovirus/genetics
11.
Molecules ; 27(6)2022 Mar 16.
Article in English | MEDLINE | ID: covidwho-1742559

ABSTRACT

The persistency of COVID-19 in the world and the continuous rise of its variants demand new treatments to complement vaccines. Computational chemistry can assist in the identification of moieties able to lead to new drugs to fight the disease. Fullerenes and carbon nanomaterials can interact with proteins and are considered promising antiviral agents. Here, we propose the possibility to repurpose fullerenes to clog the active site of the SARS-CoV-2 protease, Mpro. Through the use of docking, molecular dynamics, and energy decomposition techniques, it is shown that C60 has a substantial binding energy to the main protease of the SARS-CoV-2 virus, Mpro, higher than masitinib, a known inhibitor of the protein. Furthermore, we suggest the use of C70 as an innovative scaffold for the inhibition of SARS-CoV-2 Mpro. At odds with masitinib, both C60 and C70 interact more strongly with SARS-CoV-2 Mpro when different protonation states of the catalytic dyad are considered. The binding of fullerenes to Mpro is due to shape complementarity, i.e., vdW interactions, and is aspecific. As such, it is not sensitive to mutations that can eliminate or invert the charges of the amino acids composing the binding pocket. Fullerenic cages should therefore be more effective against the SARS-CoV-2 virus than the available inhibitors such as masinitib, where the electrostatic term plays a crucial role in the binding.


Subject(s)
COVID-19 , Fullerenes , COVID-19/drug therapy , Catalytic Domain , Cysteine Endopeptidases/chemistry , Drug Repositioning , Fullerenes/pharmacology , Humans , Peptide Hydrolases/metabolism , SARS-CoV-2 , Viral Proteins/metabolism
12.
Molecules ; 27(6)2022 Mar 09.
Article in English | MEDLINE | ID: covidwho-1732134

ABSTRACT

In the search for new anti-HIV-1 agents, two forms of phenylamino-phenoxy-quinoline derivatives have been synthesized, namely, 2-phenylamino-4-phenoxy-quinoline and 6-phenylamino-4-phenoxy-quinoline. In this study, the binding interactions of phenylamino-phenoxy-quinoline derivatives and six commercially available drugs (hydroxychloroquine, ritonavir, remdesivir, S-217622, N3, and PF-07321332) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) were investigated using molecular docking and the ONIOM method. The molecular docking showed the hydrogen bonding and hydrophobic interactions of all the compounds in the pocket of SARS-CoV-2 main protease (Mpro), which plays an important role for the division and proliferation of the virus into the cell. The binding free energy values between the ligands and Mpro ranged from -7.06 to -10.61 kcal/mol. The molecular docking and ONIOM results suggested that 4-(2',6'-dimethyl-4'-cyanophenoxy)-2-(4″-cyanophenyl)-aminoquinoline and 4-(4'-cyanophenoxy)-2-(4″-cyanophenyl)-aminoquinoline have low binding energy values and appropriate molecular properties; moreover, both compounds could bind to Mpro via hydrogen bonding and Pi-Pi stacking interactions with amino acid residues, namely, HIS41, GLU166, and GLN192. These amino acids are related to the proteolytic cleavage process of the catalytic triad mechanisms. Therefore, this study provides important information for further studies on synthetic quinoline derivatives as antiviral candidates in the treatment of SARS-CoV-2.


Subject(s)
COVID-19 , Quinolines , COVID-19/drug therapy , Cysteine Endopeptidases/chemistry , Humans , Lactams , Leucine , Molecular Docking Simulation , Nitriles , Peptide Hydrolases , Proline , Quinolines/pharmacology , SARS-CoV-2 , Viral Proteins/metabolism
13.
Bioorg Med Chem ; 49: 116415, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1415233

ABSTRACT

Dengue remains a disease of significant concern, responsible for nearly half of all arthropod-borne disease cases across the globe. Due to the lack of potent and targeted therapeutics, palliative treatment and the adoption of preventive measures remain the only available options. Compounding the problem further, the failure of the only dengue vaccine, Dengvaxia®, also delivered a significant blow to any hopes for the treatment of dengue fever. However, the success of Human Immuno-deficiency Virus (HIV) and Hepatitis C Virus (HCV) protease inhibitors in the past have continued to encourage researchers to investigate other viral protease targets. Dengue virus (DENV) NS2B-NS3 protease is an attractive target partly due to its role in polyprotein processing and also for being the most conserved domain in the viral genome. During the early days of the COVID-19 pandemic, a few cases of Dengue-COVID 19 co-infection were reported. In this review, we compared the substrate-peptide residue preferences and the residues lining the sub-pockets of the proteases of these two viruses and analyzed the significance of this similarity. Also, we attempted to abridge the developments in anti-dengue drug discovery in the last six years (2015-2020), focusing on critical discoveries that influenced the research.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Endopeptidases/metabolism , Dengue Virus/drug effects , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Coronavirus 3C Proteases/metabolism , Dengue Virus/enzymology , Humans , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology
14.
Molecules ; 25(19)2020 Oct 06.
Article in English | MEDLINE | ID: covidwho-1389458

ABSTRACT

A novel series of some hydrazones bearing thiazole moiety were generated via solvent-drop grinding of thiazole carbohydrazide 2 with various carbonyl compounds. Also, dehydrative-cyclocondensation of 2 with active methylene compounds or anhydrides gave the respective pyarzole or pyrazine derivatives. The structures of the newly synthesized compounds were established based on spectroscopic evidences and their alternative syntheses. Additionally, the anti-viral activity of all the products was tested against SARS-CoV-2 main protease (Mpro) using molecular docking combined with molecular dynamics simulation (MDS). The average binding affinities of the compounds 3a, 3b, and 3c (-8.1 ± 0.33 kcal/mol, -8.0 ± 0.35 kcal/mol, and -8.2 ± 0.21 kcal/mol, respectively) are better than that of the positive control Nelfinavir (-6.9 ± 0.51 kcal/mol). This shows the possibility of these three compounds to effectively bind to SARS-CoV-2 Mpro and hence, contradict the virus lifecycle.


Subject(s)
Antiviral Agents/chemical synthesis , Betacoronavirus/enzymology , Hydrazones/chemical synthesis , Protease Inhibitors/chemical synthesis , Pyrazines/chemical synthesis , Pyrazoles/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/pharmacology , Betacoronavirus/chemistry , Betacoronavirus/drug effects , Binding Sites , COVID-19 , Coronavirus 3C Proteases , Coronavirus Infections/drug therapy , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Drug Discovery , Humans , Hydrazones/pharmacology , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Pneumonia, Viral/drug therapy , Protease Inhibitors/pharmacology , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Pyrazines/pharmacology , Pyrazoles/pharmacology , SARS-CoV-2 , Thermodynamics , User-Computer Interface , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism
15.
Sci Adv ; 6(28): eabb8097, 2020 07.
Article in English | MEDLINE | ID: covidwho-1388430

ABSTRACT

The prevalence of respiratory illness caused by the novel SARS-CoV-2 virus associated with multiple organ failures is spreading rapidly because of its contagious human-to-human transmission and inadequate globalhealth care systems. Pharmaceutical repurposing, an effective drug development technique using existing drugs, could shorten development time and reduce costs compared to those of de novo drug discovery. We carried out virtual screening of antiviral compounds targeting the spike glycoprotein (S), main protease (Mpro), and the SARS-CoV-2 receptor binding domain (RBD)-angiotensin-converting enzyme 2 (ACE2) complex of SARS-CoV-2. PC786, an antiviral polymerase inhibitor, showed enhanced binding affinity to all the targets. Furthermore, the postfusion conformation of the trimeric S protein RBD with ACE2 revealed conformational changes associated with PC786 drug binding. Exploiting immunoinformatics to identify T cell and B cell epitopes could guide future experimental studies with a higher probability of discovering appropriate vaccine candidates with fewer experiments and higher reliability.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/immunology , Coronavirus Infections/prevention & control , Cysteine Endopeptidases/chemistry , Drug Design , Pandemics/prevention & control , Peptidyl-Dipeptidase A/chemistry , Pneumonia, Viral/prevention & control , Spike Glycoprotein, Coronavirus/chemistry , Viral Nonstructural Proteins/chemistry , Angiotensin-Converting Enzyme 2 , Benzamides , Benzazepines , Betacoronavirus/drug effects , Betacoronavirus/metabolism , Binding Sites , COVID-19 , Coronavirus 3C Proteases , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cysteine Endopeptidases/immunology , Cysteine Endopeptidases/metabolism , Drug Evaluation, Preclinical , Epitopes, B-Lymphocyte/drug effects , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/drug effects , Epitopes, T-Lymphocyte/immunology , Humans , Molecular Docking Simulation , Peptidyl-Dipeptidase A/immunology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Protein Binding , Protein Conformation , Protein Domains , Protein Interaction Domains and Motifs , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Spiro Compounds/pharmacology , Viral Nonstructural Proteins/immunology , Viral Nonstructural Proteins/metabolism
16.
Signal Transduct Target Ther ; 5(1): 221, 2020 10 06.
Article in English | MEDLINE | ID: covidwho-1387195
17.
Chem Commun (Camb) ; 57(12): 1430-1433, 2021 Feb 15.
Article in English | MEDLINE | ID: covidwho-1387498

ABSTRACT

The main viral protease (Mpro) of SARS-CoV-2 is a nucleophilic cysteine hydrolase and a current target for anti-viral chemotherapy. We describe a high-throughput solid phase extraction coupled to mass spectrometry Mpro assay. The results reveal some ß-lactams, including penicillin esters, are active site reacting Mpro inhibitors, thus highlighting the potential of acylating agents for Mpro inhibition.


Subject(s)
Antiviral Agents/pharmacology , Cysteine Endopeptidases/drug effects , Mass Spectrometry/methods , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , beta-Lactams/pharmacology , Acylation , Antiviral Agents/chemistry , COVID-19/virology , Catalytic Domain , High-Throughput Screening Assays , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology , beta-Lactams/chemistry
18.
J Med Chem ; 64(15): 11267-11287, 2021 08 12.
Article in English | MEDLINE | ID: covidwho-1319012

ABSTRACT

Cysteine proteases comprise an important class of drug targets, especially for infectious diseases such as Chagas disease (cruzain) and COVID-19 (3CL protease, cathepsin L). Peptide aldehydes have proven to be potent inhibitors for all of these proteases. However, the intrinsic, high electrophilicity of the aldehyde group is associated with safety concerns and metabolic instability, limiting the use of aldehyde inhibitors as drugs. We have developed a novel class of self-masked aldehyde inhibitors (SMAIs) for cruzain, the major cysteine protease of the causative agent of Chagas disease-Trypanosoma cruzi. These SMAIs exerted potent, reversible inhibition of cruzain (Ki* = 18-350 nM) while apparently protecting the free aldehyde in cell-based assays. We synthesized prodrugs of the SMAIs that could potentially improve their pharmacokinetic properties. We also elucidated the kinetic and chemical mechanism of SMAIs and applied this strategy to the design of anti-SARS-CoV-2 inhibitors.


Subject(s)
Aldehydes/chemistry , COVID-19/drug therapy , Chagas Disease/drug therapy , Cysteine Proteinase Inhibitors/therapeutic use , SARS-CoV-2/enzymology , Trypanosoma cruzi/enzymology , Aldehydes/metabolism , Aldehydes/pharmacology , Cathepsin L/antagonists & inhibitors , Cathepsin L/metabolism , Cysteine Endopeptidases/metabolism , Cysteine Proteases/metabolism , Cysteine Proteinase Inhibitors/chemistry , Drug Design , Humans , Kinetics , Models, Molecular , Molecular Structure , Protozoan Proteins/antagonists & inhibitors , Protozoan Proteins/metabolism , SARS-CoV-2/drug effects , Structure-Activity Relationship , Trypanosoma cruzi/drug effects
19.
J Chem Inf Model ; 61(8): 3917-3926, 2021 08 23.
Article in English | MEDLINE | ID: covidwho-1317793

ABSTRACT

The continual spread of novel coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), posing a severe threat to the health worldwide. The main protease (Mpro, alias 3CLpro) of SARS-CoV-2 is a crucial enzyme for the maturation of viral particles and is a very attractive target for designing drugs to treat COVID-19. Here, we propose a multiple conformation-based virtual screening strategy to discover inhibitors that can target SARS-CoV-2 Mpro. Based on this strategy, nine Mpro structures and a protein mimetics library with 8960 commercially available compounds were prepared to carry out ensemble docking for the first time. Five of the nine structures are apo forms presented in different conformations, whereas the other four structures are holo forms complexed with different ligands. The surface plasmon resonance assay revealed that 6 out of 49 compounds had the ability to bind to SARS-CoV-2 Mpro. The fluorescence resonance energy transfer experiment showed that the biochemical half-maximal inhibitory concentration (IC50) values of the six compounds could hamper Mpro activities ranged from 0.69 ± 0.05 to 2.05 ± 0.92 µM. Evaluation of antiviral activity using the cell-based assay indicated that two compounds (Z1244904919 and Z1759961356) could strongly inhibit the cytopathic effect and reduce replication of the living virus in Vero E6 cells with the half-maximal effective concentrations (EC50) of 4.98 ± 1.83 and 8.52 ± 0.92 µM, respectively. The mechanism of the action for the two inhibitors were further elucidated at the molecular level by molecular dynamics simulation and subsequent binding free energy analysis. As a result, the discovered noncovalent reversible inhibitors with novel scaffolds are promising antiviral drug candidates, which may be used to develop the treatment of COVID-19.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/pharmacology , Cysteine Endopeptidases , Humans , Molecular Docking Simulation , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins
20.
Expert Opin Ther Targets ; 25(6): 479-489, 2021 06.
Article in English | MEDLINE | ID: covidwho-1306504

ABSTRACT

Introduction: Enteroviruses are common viruses causing a huge number of acute and chronic infections and producing towering economic costs. Similarly, coronaviruses cause seasonal mild infections, epidemics, and even pandemics and can lead to severe respiratory symptoms. It is important to develop broadly acting antiviral molecules to efficiently tackle the infections caused by thes.Areas covered: This review illuminates the differences and similarities between enteroviruses and coronaviruses and examines the most appealing therapeutic targets to combat both virus groups. Publications of both virus groups and deposited structures discovered through PubMed to March 2021 for viral proteases have been evaluated.Expert opinion: The main protease of coronaviruses and enteroviruses share similarities in their structure and function. These proteases process their viral polyproteins and thus drugs that bind to the active site have potential to target both virus groups. It is important to develop drugs that target more evolutionarily conserved processes and proteins. Moreover, it is a wise strategy to concentrate on processes that are similar between several virus families.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus/physiology , Enterovirus/physiology , Animals , Coronavirus/drug effects , Coronavirus/enzymology , Cysteine Endopeptidases/metabolism , Enterovirus/drug effects , Enterovirus/enzymology , Humans , Substrate Specificity
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