Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 20
Filter
1.
Med Sci Monit ; 28: e934102, 2022 Jan 25.
Article in English | MEDLINE | ID: covidwho-1651076

ABSTRACT

BACKGROUND Heat-clearing and detoxifying herbs (HDHs) play an important role in the prevention and treatment of coronavirus infection. However, their mechanism of action needs further study. This study aimed to explore the anti-coronavirus basis and mechanism of HDHs. MATERIAL AND METHODS Database mining was performed on 7 HDHs. Core ingredients and targets were screened according to ADME rules combined with Neighborhood, Co-occurrence, Co-expression, and other algorithms. GO enrichment and KEGG pathway analyses were performed using the R language. Finally, high-throughput molecular docking was used for verification. RESULTS HDHs mainly acts on NOS3, EGFR, IL-6, MAPK8, PTGS2, MAPK14, NFKB1, and CASP3 through quercetin, luteolin, wogonin, indirubin alkaloids, ß-sitosterol, and isolariciresinol. These targets are mainly involved in the regulation of biological processes such as inflammation, activation of MAPK activity, and positive regulation of NF-kappaB transcription factor activity. Pathway analysis further revealed that the pathways regulated by these targets mainly include: signaling pathways related to viral and bacterial infections such as tuberculosis, influenza A, Ras signaling pathways; inflammation-related pathways such as the TLR, TNF, MAPK, and HIF-1 signaling pathways; and immune-related pathways such as NOD receptor signaling pathways. These pathways play a synergistic role in inhibiting lung inflammation and regulating immunity and antiviral activity. CONCLUSIONS HDHs play a role in the treatment of coronavirus infection by regulating the body's immunity, fighting inflammation, and antiviral activities, suggesting a molecular basis and new strategies for the treatment of COVID-19 and a foundation for the screening of new antiviral drugs.


Subject(s)
COVID-19/drug therapy , Coronavirus/drug effects , Drugs, Chinese Herbal/pharmacology , SARS-CoV-2/drug effects , Alkaloids/chemistry , Alkaloids/pharmacology , Caspase 3/drug effects , Caspase 3/genetics , Coronavirus/metabolism , Coronavirus Infections/drug therapy , Cyclooxygenase 2/drug effects , Cyclooxygenase 2/genetics , Databases, Pharmaceutical , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/therapeutic use , Flavanones/chemistry , Flavanones/pharmacology , Humans , Indoles/chemistry , Indoles/pharmacology , Interleukin-6/genetics , Lignin/chemistry , Lignin/pharmacology , Luteolin/chemistry , Luteolin/pharmacology , Mitogen-Activated Protein Kinase 14/drug effects , Mitogen-Activated Protein Kinase 14/genetics , Mitogen-Activated Protein Kinase 8/drug effects , Mitogen-Activated Protein Kinase 8/genetics , Molecular Docking Simulation , NF-kappa B p50 Subunit/drug effects , NF-kappa B p50 Subunit/genetics , Naphthols/chemistry , Naphthols/pharmacology , Nitric Oxide Synthase Type III/drug effects , Nitric Oxide Synthase Type III/genetics , Protein Interaction Maps , Quercetin/chemistry , Quercetin/pharmacology , SARS-CoV-2/metabolism , Signal Transduction , Sitosterols/chemistry , Sitosterols/pharmacology , Transcriptome/drug effects , Transcriptome/genetics
2.
Nat Commun ; 12(1): 7327, 2021 12 16.
Article in English | MEDLINE | ID: covidwho-1585856

ABSTRACT

The global disruption caused by the 2020 coronavirus pandemic stressed the supply chain of many products, including pharmaceuticals. Multiple drug repurposing studies for COVID-19 are now underway. If a winning therapeutic emerges, it is unlikely that the existing inventory of the medicine, or even the chemical raw materials needed to synthesize it, will be available in the quantities required. Here, we utilize retrosynthetic software to arrive at alternate chemical supply chains for the antiviral drug umifenovir, as well as eleven other antiviral and anti-inflammatory drugs. We have experimentally validated four routes to umifenovir and one route to bromhexine. In one route to umifenovir the software invokes conversion of six C-H bonds into C-C bonds or functional groups. The strategy we apply of excluding known starting materials from search results can be used to identify distinct starting materials, for instance to relieve stress on existing supply chains.


Subject(s)
Antiviral Agents/chemistry , COVID-19/drug therapy , Indoles/chemistry , Software , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , Drug Repositioning , Humans , Indoles/therapeutic use , SARS-CoV-2/drug effects
3.
Theranostics ; 11(14): 7005-7017, 2021.
Article in English | MEDLINE | ID: covidwho-1524524

ABSTRACT

The tumor suppressor protein p53 remains in a wild type but inactive form in ~50% of all human cancers. Thus, activating it becomes an attractive approach for targeted cancer therapies. In this regard, our lab has previously discovered a small molecule, Inauhzin (INZ), as a potent p53 activator with no genotoxicity. Method: To improve its efficacy and bioavailability, here we employed nanoparticle encapsulation, making INZ-C, an analog of INZ, to nanoparticle-encapsulated INZ-C (n-INZ-C). Results: This approach significantly improved p53 activation and inhibition of lung and colorectal cancer cell growth by n-INZ-C in vitro and in vivo while it displayed a minimal effect on normal human Wi38 and mouse MEF cells. The improved activity was further corroborated with the enhanced cellular uptake observed in cancer cells and minimal cellular uptake observed in normal cells. In vivo pharmacokinetic evaluation of these nanoparticles showed that the nanoparticle encapsulation prolongates the half-life of INZ-C from 2.5 h to 5 h in mice. Conclusions: These results demonstrate that we have established a nanoparticle system that could enhance the bioavailability and efficacy of INZ-C as a potential anti-cancer therapeutic.


Subject(s)
Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Indoles/pharmacology , Lung Neoplasms/drug therapy , Nanoparticles/chemistry , Phenothiazines/pharmacology , Tumor Suppressor Protein p53/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Biological Availability , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Humans , Indoles/chemistry , Indoles/pharmacokinetics , Indoles/therapeutic use , Mice , Mice, Inbred C57BL , Microscopy, Electron, Transmission , Nanoparticles/toxicity , Nanoparticles/ultrastructure , Phenothiazines/chemistry , Phenothiazines/pharmacokinetics , Phenothiazines/therapeutic use , Spectroscopy, Fourier Transform Infrared , Tumor Suppressor Protein p53/genetics , Xenograft Model Antitumor Assays
4.
J Med Chem ; 64(19): 14702-14714, 2021 10 14.
Article in English | MEDLINE | ID: covidwho-1412442

ABSTRACT

Here, we report the synthesis, structure-activity relationship studies, enzyme inhibition, antiviral activity, and X-ray crystallographic studies of 5-chloropyridinyl indole carboxylate derivatives as a potent class of SARS-CoV-2 chymotrypsin-like protease inhibitors. Compound 1 exhibited a SARS-CoV-2 3CLpro inhibitory IC50 value of 250 nM and an antiviral EC50 value of 2.8 µM in VeroE6 cells. Remdesivir, an RNA-dependent RNA polymerase inhibitor, showed an antiviral EC50 value of 1.2 µM in the same assay. Compound 1 showed comparable antiviral activity with remdesivir in immunocytochemistry assays. Compound 7d with an N-allyl derivative showed the most potent enzyme inhibitory IC50 value of 73 nM. To obtain molecular insight into the binding properties of these molecules, X-ray crystal structures of compounds 2, 7b, and 9d-bound to SARS-CoV 3CLpro were determined, and their binding properties were compared.


Subject(s)
Coronavirus 3C Proteases/antagonists & inhibitors , Indoles/chemistry , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/metabolism , Animals , Binding Sites , COVID-19/pathology , COVID-19/virology , Chlorocebus aethiops , Coronavirus 3C Proteases/metabolism , Crystallography, X-Ray , Humans , Indoles/chemical synthesis , Indoles/metabolism , Molecular Dynamics Simulation , Protease Inhibitors/chemical synthesis , Protease Inhibitors/metabolism , Pyridines/chemistry , SARS-CoV-2/isolation & purification , Structure-Activity Relationship , Vero Cells
5.
Viruses ; 13(8)2021 08 15.
Article in English | MEDLINE | ID: covidwho-1355053

ABSTRACT

We compared the electrostatic properties of the spike proteins (S-proteins) of three coronaviruses, SARS-CoV, MERS-CoV, and SARS-CoV-2, and their interactions with photosensitizers (PSs), octacationic octakis(cholinyl)zinc phthalocyanine (Zn-PcChol8+) and monocationic methylene blue (MB). We found a major common PS binding site at the connection of the S-protein stalk and head. The molecules of Zn-PcChol8+ and MB also form electrostatic encounter complexes with large area of negative electrostatic potential at the head of the S-protein of SARS-CoV-2, between fusion protein and heptad repeat 1 domain. The top of the SARS-CoV spike head demonstrates a notable area of electrostatic contacts with Zn-PcChol8+ and MB that corresponds to the N-terminal domain. The S-protein protomers of SARS-CoV-2 in "open" and "closed" conformations demonstrate different ability to attract PS molecules. In contrast with Zn-PcChol8+, MB possesses the ability to penetrate inside the pocket formed as a result of SARS-CoV-2 receptor binding domain transition into the "open" state. The existence of binding site for cationic PSs common to the S-proteins of SARS-CoV, SARS-CoV-2, and MERS-CoV creates prospects for the wide use of this type of PSs to combat the spread of coronaviruses.


Subject(s)
Choline/metabolism , Indoles/metabolism , Isoindoles/metabolism , Middle East Respiratory Syndrome Coronavirus/chemistry , Organometallic Compounds/metabolism , Photosensitizing Agents/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Zinc Compounds/metabolism , Binding Sites , Indoles/chemistry , Methylene Blue/metabolism , Models, Molecular , Molecular Dynamics Simulation , Organometallic Compounds/chemistry , Protein Conformation , Protein Domains , Protein Subunits/chemistry , SARS Virus/chemistry , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Static Electricity
6.
Molecules ; 26(13)2021 Jun 23.
Article in English | MEDLINE | ID: covidwho-1295887

ABSTRACT

A possible inhibitor of proteases, which contains an indole core and an aromatic polar acetylene, was designed and synthesized. This indole derivative has a molecular architecture kindred to biologically relevant species and was obtained through five synthetic steps with an overall yield of 37% from the 2,2'-(phenylazanediyl)di(ethan-1-ol). The indole derivative was evaluated through docking assays using the main protease (SARS-CoV-2-Mpro) as a molecular target, which plays a key role in the replication process of this virus. Additionally, the indole derivative was evaluated as an inhibitor of the enzyme kallikrein 5 (KLK5), which is a serine protease that can be considered as an anticancer drug target.


Subject(s)
Acetylene/chemistry , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Indoles/chemistry , Protease Inhibitors/chemistry , Protease Inhibitors/chemical synthesis , SARS-CoV-2/enzymology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Drug Discovery , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Kallikreins/antagonists & inhibitors , Models, Molecular , Molecular Docking Simulation , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects
7.
Sci Rep ; 11(1): 12410, 2021 06 14.
Article in English | MEDLINE | ID: covidwho-1268005

ABSTRACT

In situ generation of antibacterial and antiviral agents by harnessing the catalytic activity of enzymes on surfaces provides an effective eco-friendly approach for disinfection. The perhydrolase (AcT) from Mycobacterium smegmatis catalyzes the perhydrolysis of acetate esters to generate the potent disinfectant, peracetic acid (PAA). In the presence of AcT and its two substrates, propylene glycol diacetate and H2O2, sufficient and continuous PAA is generated over an extended time to kill a wide range of bacteria with the enzyme dissolved in aqueous buffer. For extended self-disinfection, however, active and stable AcT bound onto or incorporated into a surface coating is necessary. In the current study, an active, stable and reusable AcT-based coating was developed by incorporating AcT into a polydopamine (PDA) matrix in a single step, thereby forming a biocatalytic composite onto a variety of surfaces. The resulting AcT-PDA composite coatings on glass, metal and epoxy surfaces yielded up to 7-log reduction of Gram-positive and Gram-negative bacteria when in contact with the biocatalytic coating. This composite coating also possessed potent antiviral activity, and dramatically reduced the infectivity of a SARS-CoV-2 pseudovirus within minutes. The single-step approach enables rapid and facile fabrication of enzyme-based disinfectant composite coatings with high activity and stability, which enables reuse following surface washing. As a result, this enzyme-polymer composite technique may serve as a general strategy for preparing antibacterial and antiviral surfaces for applications in health care and common infrastructure safety, such as in schools, the workplace, transportation, etc.


Subject(s)
Anti-Bacterial Agents/chemistry , Antiviral Agents/chemistry , Bacterial Proteins/chemistry , Hydrolases/chemistry , Indoles/chemistry , Polymers/chemistry , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , COVID-19/pathology , COVID-19/virology , Coated Materials, Biocompatible/chemistry , Coated Materials, Biocompatible/metabolism , Coated Materials, Biocompatible/pharmacology , Drug Stability , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Humans , Hydrolases/genetics , Hydrolases/metabolism , Kinetics , Mycobacterium smegmatis/enzymology , Peracetic Acid/metabolism , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/isolation & purification , SARS-CoV-2/drug effects
8.
Viruses ; 13(4)2021 04 09.
Article in English | MEDLINE | ID: covidwho-1178430

ABSTRACT

Photodynamic inactivation of pathogenic microorganisms can be successfully used to eradicate pathogens in localized lesions, infected liquid media, and on various surfaces. This technique utilizes the photosensitizer (PS), light, and molecular oxygen to produce reactive oxygen species that kill pathogens. Here, we used the PS, water soluble octakis(cholinyl)zinc phthalocyanine (Zn-PcChol8+), to inactivate an initial 4.75-5.00 IgTCID50/mL titer of SARS-CoV-2, thereby preventing viral infection when tested in Vero E6 cell cultures. Zn-PcChol8+ in a minimally studied concentration, 1 µM and LED 3.75 J/cm2, completely destroyed the infectivity of SARS-CoV-2. To detect possible PS binding sites on the envelope of SARS-CoV-2, we analyzed electrostatic potential and simulated binding of Zn-PcChol8+ to the spike protein of this coronavirus by means of Brownian dynamics software, ProKSim (Protein Kinetics Simulator). Most of the Zn-PcChol8+ molecules formed clusters at the upper half of the stalk within a vast area of negative electrostatic potential. Positioning of the PS on the surface of the spike protein at a distance of no more than 10 nm from the viral membrane may be favorable for the oxidative damage. The high sensitivity of SARS-CoV-2 to photodynamic inactivation by Zn-PcChol8+ is discussed with respect to the application of this PS to control the spread of COVID-19.


Subject(s)
Indoles/pharmacology , Organometallic Compounds/pharmacology , Photosensitizing Agents/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/chemistry , Virus Inactivation/drug effects , Animals , COVID-19/prevention & control , Chlorocebus aethiops , Indoles/chemistry , Isoindoles , Light , Molecular Dynamics Simulation , Organometallic Compounds/chemistry , Photosensitizing Agents/chemistry , Vero Cells , Zinc Compounds
9.
Molecules ; 26(6)2021 Mar 17.
Article in English | MEDLINE | ID: covidwho-1138745

ABSTRACT

The COVID-19 outbreak continues to spread worldwide at a rapid rate. Currently, the absence of any effective antiviral treatment is the major concern for the global population. The reports of the occurrence of various point mutations within the important therapeutic target protein of SARS-CoV-2 has elevated the problem. The SARS-CoV-2 main protease (Mpro) is a major therapeutic target for new antiviral designs. In this study, the efficacy of PF-00835231 was investigated (a Mpro inhibitor under clinical trials) against the Mpro and their reported mutants. Various in silico approaches were used to investigate and compare the efficacy of PF-00835231 and five drugs previously documented to inhibit the Mpro. Our study shows that PF-00835231 is not only effective against the wild type but demonstrates a high affinity against the studied mutants as well.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Indoles/chemistry , Indoles/pharmacology , Leucine/chemistry , Leucine/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Pyrrolidinones/chemistry , Pyrrolidinones/pharmacology , Binding Sites , COVID-19/drug therapy , Computer Simulation , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/genetics , Databases, Protein , Diarylquinolines/chemistry , Diarylquinolines/pharmacology , Dihydropyridines/chemistry , Dihydropyridines/pharmacology , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Nitrobenzenes/chemistry , Nitrobenzenes/pharmacology , Nitrophenols/chemistry , Nitrophenols/pharmacology , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/pharmacology , Piperazines/chemistry , Piperazines/pharmacology , Proline/analogs & derivatives , Proline/chemistry , Proline/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/genetics
10.
Med Hypotheses ; 147: 110504, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1065481

ABSTRACT

Declared as a pandemic by the World Health Organization, COVID-19 causes damage to tissues with the cytokine storm. It even causes death in people who are fond of it. In this case, the role of the immune system is vital. In particular, the cycle of melatonin and 5-methoxytryptophol released from the pineal hormone ensures that immunity continues for 24 h. While 5-MTX is active in sunlight, melatonin secretion increases in the dark at night. 5-MTX, like melatonin, has shown antioxidant and immunomodulatory properties in studies. Therefore, people who are sick and those who are not must strictly comply with the 24-h circadian rhythm during this period. We think that it is crucial in terms of being protected from the disease that we should carry out our activities according to the circadian rhythm.


Subject(s)
COVID-19/blood , COVID-19/physiopathology , Circadian Rhythm , Indoles/blood , Sunlight , Antioxidants/metabolism , Cytokine Release Syndrome/virology , Humans , Immune System , Indoles/chemistry , Light , Melatonin/blood , Pineal Gland/metabolism
12.
Methods ; 195: 57-71, 2021 11.
Article in English | MEDLINE | ID: covidwho-1030927

ABSTRACT

SARS-CoV-2, the virus that causes COVID-19 consists of several enzymes with essential functions within its proteome. Here, we focused on repurposing approved and investigational drugs/compounds. We targeted seven proteins with enzymatic activities known to be essential at different stages of the viral cycle including PLpro, 3CLpro, RdRP, Helicase, ExoN, NendoU, and 2'-O-MT. For virtual screening, energy minimization of a crystal structure of the modeled protein was carried out using the Protein Preparation Wizard (Schrodinger LLC 2020-1). Following active site selection based on data mining and COACH predictions, we performed a high-throughput virtual screen of drugs and investigational molecules (n = 5903). The screening was performed against viral targets using three sequential docking modes (i.e., HTVS, SP, and XP). Virtual screening identified ∼290 potential inhibitors based on the criteria of energy, docking parameters, ligand, and binding site strain and score. Drugs specific to each target protein were further analyzed for binding free energy perturbation by molecular mechanics (prime MM-GBSA) and pruning the hits to the top 32 candidates. The top lead from each target pool was further subjected to molecular dynamics simulation using the Desmond module. The resulting top eight hits were tested for their SARS-CoV-2 anti-viral activity in-vitro. Among these, a known inhibitor of protein kinase C isoforms, Bisindolylmaleimide IX (BIM IX), was found to be a potent inhibitor of SARS-CoV-2. Further, target validation through enzymatic assays confirmed 3CLpro to be the target. This is the first study that has showcased BIM IX as a COVID-19 inhibitor thereby validating our pipeline.


Subject(s)
Antiviral Agents/administration & dosage , Coronavirus 3C Proteases/antagonists & inhibitors , Drug Delivery Systems/standards , Indoles/administration & dosage , Maleimides/administration & dosage , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Antiviral Agents/metabolism , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Dose-Response Relationship, Drug , Drug Delivery Systems/methods , Drug Evaluation, Preclinical/methods , Drug Repositioning/methods , Drug Repositioning/standards , High-Throughput Screening Assays/methods , High-Throughput Screening Assays/standards , Humans , Indoles/chemistry , Indoles/metabolism , Maleimides/chemistry , Maleimides/metabolism , Molecular Docking Simulation/methods , Molecular Docking Simulation/standards , Protein Structure, Secondary , Reproducibility of Results , SARS-CoV-2/chemistry
13.
Molecules ; 25(19)2020 Sep 23.
Article in English | MEDLINE | ID: covidwho-803884

ABSTRACT

The problem of treating viral infections is extremely relevant due to both the emergence of new viral diseases and to the low effectiveness of existing approaches to the treatment of known viral infections. This review focuses on the application of porphyrin, chlorin, and phthalocyanine series for combating viral infections by chemical and photochemical inactivation methods. The purpose of this review paper is to summarize the main approaches developed to date in the chemical and photodynamic inactivation of human and animal viruses using porphyrins and their analogues and to analyze and discuss the information on viral targets and antiviral activity of porphyrins, chlorins, of their conjugates with organic/inorganic compounds obtained in the last 10-15 years in order to identify the most promising areas.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Photochemotherapy/methods , Pneumonia, Viral/drug therapy , Porphyrins/pharmacology , Antiviral Agents/chemistry , COVID-19 , Humans , Indoles/chemistry , Indoles/pharmacology , Isoindoles , Pandemics , Photochemical Processes , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Porphyrins/chemistry , SARS-CoV-2 , Virus Attachment/drug effects
14.
Eur J Pharmacol ; 886: 173448, 2020 Nov 05.
Article in English | MEDLINE | ID: covidwho-1005587

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is distinctly infective and there is an ongoing effort to find a cure for this pandemic. Flavonoids exist in many diets as well as in traditional medicine, and their modern subset, indole-chalcones, are effective in fighting various diseases. Hence, these flavonoids and structurally similar indole chalcones derivatives were studied in silico for their pharmacokinetic properties including absorption, distribution, metabolism, excretion, toxicity (ADMET) and anti-SARS-CoV-2 properties against their proteins, namely, RNA dependent RNA polymerase (rdrp), main protease (Mpro) and Spike (S) protein via homology modelling and docking. Interactions were studied with respect to biology and function of SARS-CoV-2 proteins for activity. Functional/structural roles of amino acid residues of SARS-CoV-2 proteins and, the effect of flavonoid and indole chalcone interactions which may cause disease suppression are discussed. The results reveal that out of 23 natural flavonoids and 25 synthetic indole chalcones, 30 compounds are capable of Mpro deactivation as well as potentially lowering the efficiency of Mpro function. Cyanidin may inhibit RNA polymerase function and, Quercetin is found to block interaction sites on the viral spike. These results suggest flavonoids and their modern pharmaceutical cousins, indole chalcones are capable of fighting SARS-CoV-2. The in vitro anti-SARS-CoV-2 activity of these 30 compounds needs to be studied further for complete understanding and confirmation of their inhibitory potential.


Subject(s)
Betacoronavirus/drug effects , Chalcones/chemistry , Chalcones/pharmacology , Flavonoids/pharmacology , Indoles/chemistry , Molecular Docking Simulation , Viral Proteins/metabolism , Betacoronavirus/metabolism , Chalcones/metabolism , Chalcones/pharmacokinetics , Computer Simulation , Flavonoids/metabolism , Flavonoids/pharmacokinetics , Protein Conformation , SARS-CoV-2 , Safety , Tissue Distribution , Viral Proteins/chemistry
15.
Virus Res ; 289: 198146, 2020 11.
Article in English | MEDLINE | ID: covidwho-733590

ABSTRACT

The rapid emergence of novel coronavirus, SARS-coronavirus 2 (SARS-CoV-2), originated from Wuhan, China, imposed a global health emergency. Angiotensin-converting enzyme 2 (ACE2) receptor serves as an entry point for this deadly virus while the proteases like furin, transmembrane protease serine 2 (TMPRSS2) and 3 chymotrypsin-like protease (3CLpro) are involved in the further processing and replication of SARS-CoV-2. The interaction of SP with ACE2 and these proteases results in the SARS-CoV-2 invasion and fast epidemic spread. The small molecular inhibitors are reported to limit the interaction of SP with ACE2 and other proteases. Arbidol, a membrane fusion inhibitor approved for influenza virus is currently undergoing clinical trials against COVID-19. In this context, we report some analogues of arbidol designed by scaffold morphing and structure-based designing approaches with a superior therapeutic profile. The representative compounds A_BR4, A_BR9, A_BR18, A_BR22 and A_BR28 restricted the interaction of SARS-CoV-2 SP with ACE2 and host proteases furin and TMPRSS2. For 3CLPro, Compounds A_BR5, A_BR6, A_BR9 and A_BR18 exhibited high binding affinity, docking score and key residue interactions. Overall, A_BR18 and A_BR28 demonstrated multi-targeting potential against all the targets. Among these top-scoring molecules A_BR9, A_BR18, A_BR22 and A_BR28 were predicted to confer favorable ADME properties.


Subject(s)
Antiviral Agents/chemistry , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Indoles/chemistry , Pandemics , Peptidyl-Dipeptidase A/drug effects , Pneumonia, Viral/drug therapy , Receptors, Virus/drug effects , Virus Attachment/drug effects , Algorithms , Angiotensin-Converting Enzyme 2 , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Betacoronavirus/physiology , Biological Availability , COVID-19 , Drug Design , Humans , Indoles/metabolism , Indoles/pharmacology , Molecular Docking Simulation , Molecular Structure , Peptide Hydrolases/physiology , Peptidyl-Dipeptidase A/metabolism , Protein Binding , Protein Domains , Receptors, Virus/metabolism , SARS-CoV-2 , Serine Endopeptidases/drug effects , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Structure-Activity Relationship , Virus Internalization , Virus Replication
16.
mBio ; 11(4)2020 08 20.
Article in English | MEDLINE | ID: covidwho-724620

ABSTRACT

We assessed various newly generated compounds that target the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and various previously known compounds reportedly active against SARS-CoV-2, employing RNA quantitative PCR (RNA-qPCR), cytopathicity assays, and immunocytochemistry. Here, we show that two indole-chloropyridinyl-ester derivatives, GRL-0820 and GRL-0920, exerted potent activity against SARS-CoV-2 in cell-based assays performed using VeroE6 cells and TMPRSS2-overexpressing VeroE6 cells. While GRL-0820 and the nucleotide analog remdesivir blocked SARS-CoV-2 infection, viral breakthrough occurred. No significant anti-SARS-CoV-2 activity was found for several compounds reportedly active against SARS-CoV-2 such as lopinavir, nelfinavir, nitazoxanide, favipiravir, and hydroxychroloquine. In contrast, GRL-0920 exerted potent activity against SARS-CoV-2 (50% effective concentration [EC50] = 2.8 µM) and dramatically reduced the infectivity, replication, and cytopathic effect of SARS-CoV-2 without significant toxicity as examined with immunocytochemistry. Structural modeling shows that indole and chloropyridinyl of the derivatives interact with two catalytic dyad residues of Mpro, Cys145 and His41, resulting in covalent bonding, which was verified using high-performance liquid chromatography-mass spectrometry (HPLC/MS), suggesting that the indole moiety is critical for the anti-SARS-CoV-2 activity of the derivatives. GRL-0920 might serve as a potential therapeutic for coronavirus disease 2019 (COVID-19) and might be optimized to generate more-potent anti-SARS-CoV-2 compounds.IMPORTANCE Targeting the main protease (Mpro) of SARS-CoV-2, we identified two indole-chloropyridinyl-ester derivatives, GRL-0820 and GRL-0920, active against SARS-CoV-2, employing RNA-qPCR and immunocytochemistry and show that the two compounds exerted potent activity against SARS-CoV-2. While GRL-0820 and remdesivir blocked SARS-CoV-2 infection, viral breakthrough occurred as examined with immunocytochemistry. In contrast, GRL-0920 completely blocked the infectivity and cytopathic effect of SARS-CoV-2 without significant toxicity. Structural modeling showed that indole and chloropyridinyl of the derivatives interacted with two catalytic dyad residues of Mpro, Cys145 and His41, resulting in covalent bonding, which was verified using HPLC/MS. The present data should shed light on the development of therapeutics for COVID-19, and optimization of GRL-0920 based on the present data is essential to develop more-potent anti-SARS-CoV-2 compounds for treating COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Indoles/pharmacology , Pneumonia, Viral/drug therapy , Amino Acid Sequence , Animals , Betacoronavirus/enzymology , COVID-19 , Chlorocebus aethiops , Chloroquine/pharmacology , Coronavirus 3C Proteases , Coronavirus Infections/virology , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/genetics , Cysteine Endopeptidases/metabolism , Indoles/chemistry , Indoles/therapeutic use , Models, Molecular , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2 , Vero Cells , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism
17.
Comb Chem High Throughput Screen ; 24(5): 716-728, 2021.
Article in English | MEDLINE | ID: covidwho-721423

ABSTRACT

AIMS: To predict potential drugs for COVID-19 by using molecular docking for virtual screening of drugs approved for other clinical applications. BACKGROUND: SARS-CoV-2 is the betacoronavirus responsible for the COVID-19 pandemic. It was listed as a potential global health threat by the WHO due to high mortality, high basic reproduction number, and lack of clinically approved drugs and vaccines. The genome of the virus responsible for COVID-19 has been sequenced. In addition, the three-dimensional structure of the main protease has been determined experimentally. OBJECTIVE: To identify potential drugs that can be repurposed for treatment of COVID-19 by using molecular docking based virtual screening of all approved drugs. METHODS: A list of drugs approved for clinical use was obtained from the SuperDRUG2 database. The structure of the target in the apo form, as well as structures of several target-ligand complexes, were obtained from RCSB PDB. The structure of SARS-CoV-2 Mpro determined from X-ray diffraction data was used as the target. Data regarding drugs in clinical trials for COVID-19 was obtained from clinicaltrials.org. Input for molecular docking based virtual screening was prepared by using Obabel and customized python, bash, and awk scripts. Molecular docking calculations were carried out with Vina and SMINA, and the docked conformations were analyzed and visualized with PLIP, Pymol, and Rasmol. RESULTS: Among the drugs that are being tested in clinical trials for COVID-19, Danoprevir and Darunavir were predicted to have the highest binding affinity for the Main protease (Mpro) target of SARS-CoV-2. Saquinavir and Beclabuvir were identified as the best novel candidates for COVID-19 therapy by using Virtual Screening of drugs approved for other clinical indications. CONCLUSION: Protease inhibitors approved for treatment of other viral diseases have the potential to be repurposed for treatment of COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/virology , Drug Evaluation, Preclinical , Molecular Docking Simulation , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Benzazepines/chemistry , Benzazepines/pharmacology , Cyclopropanes/chemistry , Cyclopropanes/pharmacology , Darunavir/chemistry , Darunavir/pharmacology , Drug Repositioning , High-Throughput Screening Assays , Humans , Indoles/chemistry , Indoles/pharmacology , Isoindoles/chemistry , Isoindoles/pharmacology , Lactams, Macrocyclic/chemistry , Lactams, Macrocyclic/pharmacology , Proline/analogs & derivatives , Proline/chemistry , Proline/pharmacology , Saquinavir/chemistry , Saquinavir/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology
18.
Virus Res ; 286: 198068, 2020 09.
Article in English | MEDLINE | ID: covidwho-603573

ABSTRACT

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a renewed interest in studying the role of the spike S glycoprotein in regulating coronavirus infections in the natural host. Taking advantage of the cryo-electron microscopy structure of SARS-CoV-2 S trimer in the prefusion conformation, we performed a virtual screening simulation with the aim to identify novel molecules that could be used as fusion inhibitors. The spike glycoprotein structure has been completed using modeling techniques and its inner cavity, needful for the postfusion transition of the trimer, has been scanned for the identification of strongly interacting available drugs. Finally, the stability of the protein-drug top complexes has been tested using classical molecular dynamics simulations. The free energy of interaction of the molecules to the spike protein has been evaluated through the MM/GBSA method and per-residue decomposition analysis. Results have been critically discussed considering previous scientific knowledge concerning the selected compounds and sequence alignments have been carried out to evaluate the spike glycoprotein similarity among the betacoronavirus family members. Finally, a cocktail of drugs that may be used as SARS-CoV-2 fusion inhibitors has been suggested.


Subject(s)
Antiviral Agents/chemistry , Betacoronavirus/chemistry , Heterocyclic Compounds, 4 or More Rings/chemistry , Indoles/chemistry , Perylene/analogs & derivatives , Spike Glycoprotein, Coronavirus/chemistry , Sulfonamides/chemistry , Anthracenes , Antiviral Agents/pharmacology , Betacoronavirus/pathogenicity , Binding Sites , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Gene Expression , Heterocyclic Compounds, 4 or More Rings/pharmacology , High-Throughput Screening Assays , Humans , Indoles/pharmacology , Isoindoles , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Perylene/chemistry , Perylene/pharmacology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Protein Multimerization , SARS-CoV-2 , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Sulfonamides/pharmacology , Thermodynamics , User-Computer Interface , Virus Internalization/drug effects
19.
Int J Antimicrob Agents ; 56(2): 105998, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-291695

ABSTRACT

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic is a global public health emergency, and new therapeutics are needed. This article reports the potential drug target and mechanism of action of Arbidol (umifenovir) to treat coronavirus disease 2019 (COVID-19). Molecular dynamics and structural analysis were used to show how Arbidol targets the SARS-CoV-2 spike glycoprotein and impedes its trimerization, which is key for host cell adhesion and hijacking, indicating the potential of Arbidol to treat COVID-19. It is hoped that knowledge of the potential drug target and mechanism of action of Arbidol will help in the development of new therapeutics for SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Biopolymers/chemistry , Coronavirus Infections/drug therapy , Indoles/pharmacology , Pneumonia, Viral/drug therapy , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Antiviral Agents/therapeutic use , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/virology , Humans , Indoles/chemistry , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2
20.
J Med Chem ; 63(6): 3131-3141, 2020 03 26.
Article in English | MEDLINE | ID: covidwho-2598

ABSTRACT

Structure-based stabilization of protein-protein interactions (PPIs) is a promising strategy for drug discovery. However, this approach has mainly focused on the stabilization of native PPIs, and non-native PPIs have received little consideration. Here, we identified a non-native interaction interface on the three-dimensional dimeric structure of the N-terminal domain of the MERS-CoV nucleocapsid protein (MERS-CoV N-NTD). The interface formed a conserved hydrophobic cavity suitable for targeted drug screening. By considering the hydrophobic complementarity during the virtual screening step, we identified 5-benzyloxygramine as a new N protein PPI orthosteric stabilizer that exhibits both antiviral and N-NTD protein-stabilizing activities. X-ray crystallography and small-angle X-ray scattering showed that 5-benzyloxygramine stabilizes the N-NTD dimers through simultaneous hydrophobic interactions with both partners, resulting in abnormal N protein oligomerization that was further confirmed in the cell. This unique approach based on the identification and stabilization of non-native PPIs of N protein could be applied toward drug discovery against CoV diseases.


Subject(s)
Alkaloids/pharmacology , Antiviral Agents/pharmacology , Indoles/pharmacology , Nucleocapsid Proteins/metabolism , Protein Multimerization/drug effects , Alkaloids/chemistry , Alkaloids/metabolism , Amino Acid Sequence , Animals , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Chlorocebus aethiops , Coronavirus Nucleocapsid Proteins , Crystallography, X-Ray , Drug Design , Hydrophobic and Hydrophilic Interactions , Indoles/chemistry , Indoles/metabolism , Middle East Respiratory Syndrome Coronavirus/chemistry , Middle East Respiratory Syndrome Coronavirus/drug effects , Molecular Docking Simulation , Nucleocapsid Proteins/chemistry , Protein Binding , Protein Domains , Sequence Alignment , Vero Cells
SELECTION OF CITATIONS
SEARCH DETAIL