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1.
Asian Pac J Cancer Prev ; 23(9): 3113-3123, 2022 Sep 01.
Article in English | MEDLINE | ID: covidwho-2205791

ABSTRACT

BACKGROUND: This study was carried out to synthesize a new complex of Fe(II) with isoleucine dithiocarbamate ligand and to determine its potential as an anticancer and antiviral agent for SARSCOV-2. METHODS: The synthesized complexes were then characterized by UV-vis and FT-IR spectroscopy and their melting points. The value of the conductivity of the complex compound is also determined. Anti-cancer activity was tested in vitro and molecular docking. Its potential as an antiviral against SARSCOV-2 was also carried out by molecular docking. Pharmacokinetics/ADMET properties were also carried out on the complex. RESULT: Spectral results showed the successful synthesis of Fe(II) isoleucine dithiocarbamate complex. The complex produced UV-vis spectra at 268 and 575 nm, and the IR data at 399-599 cm-1 showed the coordination between the Fe(II) atoms with sulphur, nitrogen and oxygen of the isoleucine dithiocarbamate ligand. Fe(II) isoleucine dithiocarbamate had a cytotoxicity effect on the MCF-7 cell line (IC50 =613 µg/mL). The complex significantly caused morphological changes in the breast cancer cell line, finally leading to cell apoptosis. CONCLUSION: Cytotoxic test of Fe(II) isoleucine dithiocarbamate showed moderate anticancer activity on MCF-7 cancer cells and showed antiviral activity against SARSCOV-2 by interfering with spike glycoprotein -ACE2 receptors, and inhibiting major proteases and 3Clpro.


Subject(s)
Antineoplastic Agents , COVID-19 , Coordination Complexes , Angiotensin-Converting Enzyme 2 , Antineoplastic Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Coordination Complexes/pharmacology , Ferrous Compounds , Humans , Isoleucine , Ligands , Molecular Docking Simulation , Nitrogen , Oxygen , Spectroscopy, Fourier Transform Infrared , Sulfur
2.
Molecules ; 27(22)2022 Nov 21.
Article in English | MEDLINE | ID: covidwho-2123759

ABSTRACT

This work identifies new ligands of the nucleoprotein N of SARS-CoV-2 by in silico screening, which used a new model of N, built from an Alphafold model refined by molecular dynamic simulations. The ligands were neuropeptides, such as substance P (1-7) and enkephalin, bound at a large site of the C-terminal or associated with the N-terminal ß-sheet. The BA4 and BA5 Omicron variants of N also exhibited a large site as in wt N, and an increased flexibility of the BA5 variant, enabling substance P binding. The binding sites of some ligands deduced from modeling in wt N were assessed by mutation studies in surface plasmon resonance experiments. Dynamic light scattering showed that the ligands impeded RNA binding to N, which likely inhibited replication. We suggest that the physiological role of these neuropeptides in neurotransmission, pain and vasodilation for cholecystokinin and substance P could be altered by binding to N. We speculate that N may link between viral replication and multiple pathways leading to long COVID-19 symptoms. Therefore, N may constitute a "danger hub" that needs to be inhibited, even at high cost for the host. Antivirals targeted to N may therefore reduce the risk of brain fog and stroke, and improve patients' health.


Subject(s)
COVID-19 , Neuropeptides , Humans , Nucleoproteins , SARS-CoV-2 , Ligands , Substance P , Synaptic Transmission , Inflammation
3.
Nano Lett ; 22(22): 8932-8940, 2022 Nov 23.
Article in English | MEDLINE | ID: covidwho-2106310

ABSTRACT

Plasmonic coupling via nanoparticle assembly is a popular signal-generation method in bioanalytical sensors. Here, we customized an all-peptide-based ligand that carries an anchoring group, polyproline spacer, biomolecular recognition, and zwitterionic domains for functionalizing gold nanoparticles (AuNPs) as a colorimetric enzyme sensor. Our results underscore the importance of the polyproline module, which enables the SARS-CoV-2 main protease (Mpro) to recognize the peptidic ligand on nanosurfaces for subsequent plasmonic coupling via Coulombic interactions. AuNP aggregation is favored by the lowered surface potential due to enzymatic unveiling of the zwitterionic module. Therefore, this system provides a naked-eye measure for Mpro. No proteolysis occurs on AuNPs modified with a control ligand lacking a spacer domain. Overall, this all-peptide-based ligand does not require complex molecular conjugations and hence offers a simple and promising route for plasmonic sensing other proteases.


Subject(s)
COVID-19 , Metal Nanoparticles , Humans , Gold , Surface Plasmon Resonance/methods , Ligands , SARS-CoV-2 , Peptides
4.
SAR QSAR Environ Res ; 33(10): 753-778, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-2096975

ABSTRACT

Since interleukin-8 (IL-8/CXCL8) and its receptor, CXCR1 and CXCR2, were known in the early 1990s, biological pathways related to these proteins were proven to have high clinical value in cancer and inflammatory/autoimmune conditions treatment. Recently, IL-8 has been identified as biomarker for severe COVID-19 patients and COVID-19 prognosis. Boyles et al. (mAbs 12 (2020), pp. 1831880) have published a high-resolution X-ray crystal structure of the LY3041658 Fab in a complex human CXCL8. They described the ability to bind to IL-8 and the blocking of IL-8/its receptors interaction by the LY3041658 monoclonal antibody. Therefore, the study has been designed to identify potential small molecules inhibiting interleukin-8 by targeting LY3041658/IL-8 complex structure using an in silico approach. A structure­based pharmacophore and molecular docking models of the protein active site cavity were generated to identify possible candidates, followed by virtual screening with the ZINC database. ADME analysis of hit compounds was also conducted. Molecular dynamics simulations were then performed to survey the behaviour and stability of the ligand-protein complexes. Furthermore, the MM/PBSA technique has been utilized to evaluate the free binding energy. The final data confirmed that one newly obtained compound, ZINC21882765, may serve as the best potential inhibitor for IL-8.


Subject(s)
COVID-19 , Interleukin-8 , Humans , Molecular Docking Simulation , Quantitative Structure-Activity Relationship , COVID-19/drug therapy , Molecular Dynamics Simulation , Ligands
5.
Sci Rep ; 12(1): 18500, 2022 Nov 02.
Article in English | MEDLINE | ID: covidwho-2096797

ABSTRACT

The nucleocapsid (N) protein plays critical roles in coronavirus genome transcription and packaging, representing a key target for the development of novel antivirals, and for which structural information on ligand binding is scarce. We used a novel fluorescence polarization assay to identify small molecules that disrupt the binding of the N protein to a target RNA derived from the SARS-CoV-2 genome packaging signal. Several phenolic compounds, including L-chicoric acid (CA), were identified as high-affinity N-protein ligands. The binding of CA to the N protein was confirmed by isothermal titration calorimetry, 1H-STD and 15N-HSQC NMR, and by the crystal structure of CA bound to the N protein C-terminal domain (CTD), further revealing a new modulatory site in the SARS-CoV-2 N protein. Moreover, CA reduced SARS-CoV-2 replication in cell cultures. These data thus open venues for the development of new antivirals targeting the N protein, an essential and yet underexplored coronavirus target.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Ligands , Nucleocapsid Proteins/genetics , RNA/metabolism , Antiviral Agents/pharmacology , Protein Binding
6.
J Chem Inf Model ; 62(22): 5715-5728, 2022 Nov 28.
Article in English | MEDLINE | ID: covidwho-2096619

ABSTRACT

The prediction of ligand efficacy has long been linked to thermodynamic properties such as the equilibrium dissociation constant, which considers both the association and the dissociation rates of a defined protein-ligand complex. In the last 15 years, there has been a paradigm shift, with an increased interest in the determination of kinetic properties such as the drug-target residence time since they better correlate with ligand efficacy compared to other parameters. In this article, we present thermal titration molecular dynamics (TTMD), an alternative computational method that combines a series of molecular dynamics simulations performed at progressively increasing temperatures with a scoring function based on protein-ligand interaction fingerprints for the qualitative estimation of protein-ligand-binding stability. The protocol has been applied to four different pharmaceutically relevant test cases, including protein kinase CK1δ, protein kinase CK2, pyruvate dehydrogenase kinase 2, and SARS-CoV-2 main protease, on a variety of ligands with different sizes, structures, and experimentally determined affinity values. In all four cases, TTMD was successfully able to distinguish between high-affinity compounds (low nanomolar range) and low-affinity ones (micromolar), proving to be a useful screening tool for the prioritization of compounds in a drug discovery campaign.


Subject(s)
COVID-19 , Molecular Dynamics Simulation , Humans , Ligands , Protein Binding , SARS-CoV-2
7.
Opt Express ; 30(22): 40277-40291, 2022 Oct 24.
Article in English | MEDLINE | ID: covidwho-2089309

ABSTRACT

We conceptualized and numerically investigated a photonic crystal fiber (PCF)-based surface plasmon resonance (SPR) sensor for rapid detection and quantification of novel coronavirus. The plasmonic gold-based optical sensor permits three different ways to quantify the virus concentrations inside patient's body based on different ligand-analyte conjugate pairs. This photonic biosensor demonstrates viable detections of SARS-CoV-2 spike receptor-binding-domain (RBD), mutated viral single-stranded ribonucleic acid (RNA) and human monoclonal antibody immunoglobulin G (IgG). A marquise-shaped core is introduced to facilitate efficient light-tailoring. Analytes are dissolved in sterile phosphate buffered saline (PBS) and surfaced on the plasmonic metal layer for realizing detection. The 1-pyrene butyric acid n-hydroxy-succinimide ester is numerically used to immobilize the analytes on the sensing interface. Using the finite element method (FEM), the proposed sensor is studied critically and optimized for the refractive index (RI) range from 1.3348-1.3576, since the target analytes RIs fluctuate within this range depending on the severity of the viral infection. The polarization-dependent sensor exhibits dominant sensing attributes for x-polarized mode, where it shows the average wavelength sensitivities of 2,009 nm/RIU, 2,745 nm/RIU and 1,984 nm/RIU for analytes: spike RBD, extracted coronavirus RNA and antibody IgG, respectively. The corresponding median amplitude sensitivities are 135 RIU-1, 196 RIU-1 and 140 RIU-1, respectively. The maximum sensor resolution and figure of merit are found 2.53 × 10-5 RIU and 101 RIU-1, respectively for viral RNA detection. Also, a significant limit of detection (LOD) of 6.42 × 10-9 RIU2/nm is obtained. Considering modern bioassays, the proposed compact photonic sensor will be well-suited for rapid point-of-care COVID testing.


Subject(s)
Biosensing Techniques , COVID-19 , Humans , SARS-CoV-2 , Ligands , Butyric Acid , COVID-19 Testing , RNA, Viral , COVID-19/diagnosis , Gold/chemistry , Immunoglobulin G , Succinimides , Pyrenes , Antibodies, Monoclonal , Esters , Phosphates
8.
Sci Adv ; 8(43): eabq6207, 2022 10 28.
Article in English | MEDLINE | ID: covidwho-2088381

ABSTRACT

The frequent occurrence of viral variants is a critical problem in developing antiviral prophylaxis and therapy; along with stronger recognition of host cell receptors, the variants evade the immune system-based vaccines and neutralizing agents more easily. In this work, we focus on enhanced receptor binding of viral variants and demonstrate generation of receptor-mimicking synthetic reagents, capable of strongly interacting with viruses and their variants. The hotspot interaction of viruses with receptor-derived short peptides is maximized by aptamer-like scaffolds, the compact and stable architectures of which can be in vitro selected from a myriad of the hotspot peptide-coupled random nucleic acids. We successfully created the human angiotensin-converting enzyme 2 (hACE2) receptor-mimicking hybrid ligand that recruits the hACE2-derived receptor binding domain-interacting peptide to directly interact with a binding hotspot of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Experiencing affinity boosting by ~500% to Omicron, the de novo selected hACE2 mimic exhibited a great binding tolerance to all SARS-CoV-2 variants of concern.


Subject(s)
COVID-19 , Nucleic Acids , Humans , Angiotensin-Converting Enzyme 2/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Ligands , Receptors, Virus/metabolism , Peptidyl-Dipeptidase A/metabolism , Protein Binding , Peptides/metabolism , Antiviral Agents
9.
Proc Natl Acad Sci U S A ; 119(44): e2204242119, 2022 11.
Article in English | MEDLINE | ID: covidwho-2087415

ABSTRACT

The pathophysiological mechanisms underlying the constellation of symptoms that characterize COVID-19 are only incompletely understood. In an effort to fill these gaps, a "nicotinic hypothesis," which posits that nicotinic acetylcholine receptors (AChRs) act as additional severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptors, has recently been put forth. A key feature of the proposal (with potential clinical ramifications) is the suggested competition between the virus' spike protein and small-molecule cholinergic ligands for the receptor's orthosteric binding sites. This notion is reminiscent of the well-established role of the muscle AChR during rabies virus infection. To address this hypothesis directly, we performed equilibrium-type ligand-binding competition assays using the homomeric human α7-AChR (expressed on intact cells) as the receptor, and radio-labeled α-bungarotoxin (α-BgTx) as the orthosteric-site competing ligand. We tested different SARS-CoV-2 spike protein peptides, the S1 domain, and the entire S1-S2 ectodomain, and found that none of them appreciably outcompete [125I]-α-BgTx in a specific manner. Furthermore, patch-clamp recordings showed no clear effect of the S1 domain on α7-AChR-mediated currents. We conclude that the binding of the SARS-CoV-2 spike protein to the human α7-AChR's orthosteric sites-and thus, its competition with ACh, choline, or nicotine-is unlikely to be a relevant aspect of this complex disease.


Subject(s)
COVID-19 , Receptors, Nicotinic , Humans , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Bungarotoxins , Nicotine , alpha7 Nicotinic Acetylcholine Receptor , Ligands , SARS-CoV-2 , Receptors, Nicotinic/metabolism , Cholinergic Agents , Choline
10.
Sci Rep ; 12(1): 17984, 2022 Oct 26.
Article in English | MEDLINE | ID: covidwho-2087304

ABSTRACT

Parallel cascade selection molecular dynamics-based ligand binding-path sampling (LB-PaCS-MD) was combined with fragment molecular orbital (FMO) calculations to reveal the ligand path from an aqueous solution to the SARS-CoV-2 main protease (Mpro) active site and to customise a ligand-binding pocket suitable for delivering a potent inhibitor. Rubraxanthone exhibited mixed-inhibition antiviral activity against SARS-CoV-2 Mpro, relatively low cytotoxicity, and high cellular inhibition. However, the atomic inhibition mechanism remains ambiguous. LB-PaCS-MD/FMO is a hybrid ligand-binding evaluation method elucidating how rubraxanthone interacts with SARS-CoV-2 Mpro. In the first step, LB-PaCS-MD, which is regarded as a flexible docking, efficiently samples a set of ligand-binding pathways. After that, a reasonable docking pose of LB-PaCS-MD is evaluated by the FMO calculation to elucidate a set of protein-ligand interactions, enabling one to know the binding affinity of a specified ligand with respect to a target protein. A possible conformation was proposed for rubraxanthone binding to the SARS-CoV-2 Mpro active site, and allosteric inhibition was elucidated by combining blind docking with k-means clustering. The interaction profile, key binding residues, and considerable interaction were elucidated for rubraxanthone binding to both Mpro sites. Integrated LB-PaCS-MD/FMO provided a more reasonable complex structure for ligand binding at the SARS-CoV-2 Mpro active site, which is vital for discovering and designing antiviral drugs.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Ligands , Protease Inhibitors/chemistry , COVID-19/drug therapy , Viral Nonstructural Proteins/metabolism , Molecular Docking Simulation , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Molecular Dynamics Simulation
11.
Eur J Intern Med ; 105: 1-7, 2022 11.
Article in English | MEDLINE | ID: covidwho-2086143

ABSTRACT

Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare syndrome characterized by high-titer anti-platelet factor 4 (PF4) antibodies, thrombocytopenia and arterial and venous thrombosis in unusual sites, as cerebral venous sinuses and splanchnic veins. VITT has been described to occur almost exclusively after administration of ChAdOx1 nCoV-19 and Ad26.COV2.S adenovirus vector- based COVID-19 vaccines. Clinical and laboratory features of VITT resemble those of heparin-induced thrombocytopenia (HIT). It has been hypothesized that negatively charged polyadenylated hexone proteins of the AdV vectors could act as heparin to induce the conformational changes of PF4 molecule that lead to the formation of anti-PF4/polyanion antibodies. The anti-PF4 immune response in VITT is fostered by the presence of a proinflammatory milieu, elicited by some impurities found in ChAdOx1 nCoV-19 vaccine, as well as by soluble spike protein resulting from alternative splice events. Anti-PF4 antibodies bind PF4, forming immune complexes which activate platelets, monocytes and granulocytes, resulting in the VITT's immunothrombosis. The reason why only a tiny minority of patents receiving AdV-based COVID-19 vaccines develop VITT is still unknown. It has been hypothesized that individual intrinsic factors, either acquired (i.e., pre-priming of B cells to produce anti-PF4 antibodies by previous contacts with bacteria or viruses) or inherited (i.e., differences in platelet T-cell ubiquitin ligand-2 [TULA-2] expression) can predispose a few subjects to develop VITT. A better knowledge of the mechanistic basis of VITT is essential to improve the safety and the effectiveness of future vaccines and gene therapies using adenovirus vectors.


Subject(s)
COVID-19 , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Thrombosis , Vaccines , Humans , Antigen-Antibody Complex , COVID-19 Vaccines/adverse effects , Ad26COVS1 , ChAdOx1 nCoV-19 , Ligands , Spike Glycoprotein, Coronavirus , COVID-19/prevention & control , Platelet Factor 4/genetics , Platelet Factor 4/metabolism , Heparin/adverse effects , Thrombocytopenia/chemically induced , Vaccines/adverse effects , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Ubiquitins
12.
Curr Top Microbiol Immunol ; 436: 437-466, 2022.
Article in English | MEDLINE | ID: covidwho-2075205

ABSTRACT

A number of different experimental models using both non-selective and selective PI3K inhibitors have shown that many pathogenic steps of respiratory disorders, such as bronchial asthma, Chronic Obstructive Pulmonary Disease (COPD), Idiopathic Pulmonary Fibrosis (IPF), Acute Respiratory Distress Syndrome (ARDS) and Lung Cancer (LC) are, at least in part, regulated by the PI3K signaling pathway, suggesting that the inhibition of PI3K could represent an ideal therapeutic target for the treatment of respiratory diseases. This chapter summarizes the current state of the therapeutic strategies aimed to exploit the inhibition of PI3K in this context. In animal models of asthma, selective δ and γ inhibitors have shown to be effective, and when administered by inhalation, reasonably safe. Nevertheless, very few clinical trials have been performed so far. The efficacy of current traditional therapies for allergic bronchial asthma has likely diminished the need for new alternative treatments. Surprisingly, in COPD, where instead there is an urgent need for new and more effective therapeutic approaches, the number of clinical studies is still low and not capable yet, with the exception for an acceptable safety profile, to show a significant improvement of clinical outcomes. In IPF, a disease with a disappointing prognosis, PI3K inhibitors have been bound to a FAP ligand with the aim to selectively target myofibroblasts, showing to significantly reduce collagen production and the development of lung fibrosis in an animal model of lung fibrosis. Due to its role in cell activation and cell replication, the PI3K pathway is obviously largely involved in lung cancer. Several studies, currently ongoing, are testing the effect of PI3K inhibitors mainly in NSCLC. Some evidence in the treatment of cancer patients suggests the possibility that PI3K inhibitors may enhance the response to conventional treatment. The involvement of PI3Kδ in the modulation of airway neutrophil recruitment and bronchial epithelial functional alterations also suggest a potential role in the treatment of ARDS, but at the current state the ongoing trials are aimed to the treatment of ARDS in COVID-19 patients. In general, few clinical trials investigating PI3K inhibitors in respiratory disorders have been performed so far. This relatively new approach of treatment is just at its beginning and certainly needs further efforts and additional studies.


Subject(s)
Asthma , COVID-19 , Idiopathic Pulmonary Fibrosis , Lung Neoplasms , Pulmonary Disease, Chronic Obstructive , Respiratory Distress Syndrome , Animals , Asthma/drug therapy , Collagen/therapeutic use , Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/metabolism , Idiopathic Pulmonary Fibrosis/pathology , Ligands , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Pulmonary Disease, Chronic Obstructive/drug therapy , Respiratory Distress Syndrome/drug therapy
13.
J Clin Lab Anal ; 36(11): e24725, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2075024

ABSTRACT

It is well known that people's health is seriously threatened by various pathogens (such as Mycobacterium tuberculosis, Treponema pallidum, Novel coronavirus, HIV, Mucor, etc.), which leads to heavy socioeconomic burdens. Therefore, early and accurate pathogen diagnosis is essential for timely and effective therapies. Up to now, diagnosing human contagious diseases at molecule and nano levels is remarkably difficult owing to insufficient valid probes when it comes to determining the biological markers of pathogens. Aptamers are a set of high-specificity and high-sensitivity plastic oligonucleotides screened in vitro via the selective expansion of ligands by exponential enrichment (SELEX). With the advent of aptamer-based technologies, their merits have aroused mounting academic interest. In recent years, as new detection and treatment tools, nucleic acid aptamers have been extensively utilized in the field of biomedicine, such as pathogen detection, new drug development, clinical diagnosis, nanotechnology, etc. However, the traditional SELEX method is cumbersome and has a long screening cycle, and it takes several months to screen out aptamers with high specificity. With the persistent development of SELEX-based aptamer screening technologies, the application scenarios of aptamers have become more and more extensive. The present research briefly reviews the research progress of nucleic acid aptamers in the field of biomedicine, especially in the diagnosis of contagious diseases.


Subject(s)
Aptamers, Nucleotide , COVID-19 , Mycobacterium tuberculosis , Nucleic Acids , Humans , SELEX Aptamer Technique/methods , COVID-19/diagnosis , Ligands
14.
Molecules ; 27(20)2022 Oct 12.
Article in English | MEDLINE | ID: covidwho-2071650

ABSTRACT

COVID-19 can cause different neurological symptoms in some people, including smell, inability to taste, dizziness, confusion, delirium, seizures, stroke, etc. Owing to the issue of vaccine effectiveness, update and coverage, we still need one or more diversified strategies as the backstop to manage illness. Characterizing the structural basis of ligand recognition in the main protease (Mpro) of SARS-CoV-2 will facilitate its rational design and development of potential drug candidates with high affinity and selectivity against COVID-19. Up to date, covalent-, non-covalent inhibitors and allosteric modulators have been reported to bind to different active sites of Mpro. In the present work, we applied the molecular dynamics (MD) simulations to systematically characterize the potential binding features of catalytic active site and allosteric binding sites in Mpro using a dataset of 163 3D structures of Mpro-inhibitor complexes, in which our results are consistent with the current studies. In addition, umbrella sampling (US) simulations were used to explore the dissociation processes of substrate pathway and allosteric pathway. All the information provided new insights into the protein features of Mpro and will facilitate its rational drug design for COVID-19.


Subject(s)
COVID-19 , Molecular Dynamics Simulation , Humans , SARS-CoV-2 , COVID-19/drug therapy , Ligands , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/metabolism , Coronavirus 3C Proteases , Molecular Docking Simulation , Antiviral Agents/pharmacology , Antiviral Agents/chemistry
15.
Int J Mol Sci ; 23(20)2022 Oct 18.
Article in English | MEDLINE | ID: covidwho-2071518

ABSTRACT

The regular reappearance of coronavirus (CoV) outbreaks over the past 20 years has caused significant health consequences and financial burdens worldwide. The most recent and still ongoing novel CoV pandemic, caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has brought a range of devastating consequences. Due to the exceptionally fast development of vaccines, the mortality rate of the virus has been curbed to a significant extent. However, the limitations of vaccination efficiency and applicability, coupled with the still high infection rate, emphasise the urgent need for discovering safe and effective antivirals against SARS-CoV-2 by suppressing its replication or attenuating its virulence. Non-structural protein 1 (nsp1), a unique viral and conserved leader protein, is a crucial virulence factor for causing host mRNA degradation, suppressing interferon (IFN) expression and host antiviral signalling pathways. In view of the essential role of nsp1 in the CoV life cycle, it is regarded as an exploitable target for antiviral drug discovery. Here, we report a variety of fragment hits against the N-terminal domain of SARS-CoV-2 nsp1 identified by fragment-based screening via X-ray crystallography. We also determined the structure of nsp1 at atomic resolution (0.99 Å). Binding affinities of hits against nsp1 and potential stabilisation were determined by orthogonal biophysical assays such as microscale thermophoresis and thermal shift assays. We identified two ligand-binding sites on nsp1, one deep and one shallow pocket, which are not conserved between the three medically relevant SARS, SARS-CoV-2 and MERS coronaviruses. Our study provides an excellent starting point for the development of more potent nsp1-targeting inhibitors and functional studies on SARS-CoV-2 nsp1.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Viral Nonstructural Proteins/metabolism , Ligands , X-Rays , Binding Sites , Antiviral Agents/pharmacology , Interferons , Virulence Factors
16.
Biosensors (Basel) ; 12(10)2022 Oct 17.
Article in English | MEDLINE | ID: covidwho-2071230

ABSTRACT

In March 2020, the World Health Organization (WHO) declared COVID-19 a pandemic, and the spike protein has been reported to be an important drug target for anti-COVID-19 treatment. As such, in this study, we successfully developed a novel electrochemical receptor biosensor by immobilizing the SARS-CoV-2 spike protein and using AuNPs-HRP as an electrochemical signal amplification system. Moreover, the time-current method was used to quantify seven antiviral drug compounds, such as arbidol and chloroquine diphosphate. The results show that the spike protein and the drugs are linearly correlated within a certain concentration range and that the detection sensitivity of the sensor is extremely high. In the low concentration range of linear response, the kinetics of receptor-ligand interactions are similar to that of an enzymatic reaction. Among the investigated drug molecules, bromhexine exhibits the smallest Ka value, and thus, is most sensitively detected by the sensor. Hydroxychloroquine exhibits the largest Ka value. Molecular docking simulations of the spike protein with six small-molecule drugs show that residues of this protein, such as Asp, Trp, Asn, and Gln, form hydrogen bonds with the -OH or -NH2 groups on the branched chains of small-molecule drugs. The electrochemical receptor biosensor can directly quantify the interaction between the spike protein and drugs such as abidor and hydroxychloroquine and perform kinetic studies with a limit of detection 3.3 × 10-20 mol/L, which provides a new research method and idea for receptor-ligand interactions and pharmacodynamic evaluation.


Subject(s)
Bromhexine , COVID-19 , Metal Nanoparticles , Humans , Spike Glycoprotein, Coronavirus/chemistry , Hydroxychloroquine/pharmacology , SARS-CoV-2 , Molecular Docking Simulation , Kinetics , Ligands , Gold , Antiviral Agents/pharmacology
17.
Molecules ; 27(19)2022 Oct 09.
Article in English | MEDLINE | ID: covidwho-2066287

ABSTRACT

The main protease enzyme (Mpro) of SARS-CoV-2 is one of the most promising targets for COVID-19 treatment. Accordingly, in this work, a structure-based virtual screening of 3.8 million ligand libraries was carried out. After rigorous filtering, docking, and post screening assessments, 78 compounds were selected for biological evaluation, 3 of which showed promising inhibition of the Mpro enzyme. The obtained hits (CB03, GR04, and GR20) had reasonable potencies with Ki values in the medium to high micromolar range. Interestingly, while our most potent hit, GR20, was suggested to act via a reversible covalent mechanism, GR04 was confirmed as a noncompetitive inhibitor that seems to be one of a kind when compared to the other allosteric inhibitors discovered so far. Moreover, all three compounds have small sizes (~300 Da) with interesting fittings in their relevant binding sites, and they possess lead-like characteristics that can introduce them as very attractive candidates for the future development of COVID-19 treatments.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Catalytic Domain , Coronavirus 3C Proteases , Humans , Ligands , Molecular Docking Simulation , Protease Inhibitors/chemistry
18.
Molecules ; 27(19)2022 Oct 03.
Article in English | MEDLINE | ID: covidwho-2066283

ABSTRACT

Honey inhibits bacterial growth due to the high sugar concentration, hydrogen peroxide generation, and proteinaceous compounds present in it. In this study, the antibacterial activity of stingless and sting honey against foodborne pathogenic bacteria isolated from spoiled milk samples was examined. The isolated bacterial strains were confirmed as Bacillus cereus and Listeriamonocytogenes through morphological, biochemical, and 16 s RNA analysis. Physiochemical characterizations of the honey samples revealed that both of the honey samples had an acidic pH, low water content, moderate reducing sugar content, and higher proline content. Through the disc diffusion method, the antibacterial activities of the samples were assayed and better results were observed for the 50 mg/disc honey. Both stingless and sting honey showed the most positive efficacy against Bacillus cereus. Therefore, an in silico study was conducted against this bacterium with some common compounds of honey. From several retrieved constituents of stingless and sting honey, 2,4-dihydroxy-2,5-dimethyl 3(2H)-furan-3-one (furan) and 4H-pyran-4-one,2,3-dihydro of both samples and beta.-D-glucopyranose from the stingless revealed high ligand-protein binding efficiencies for the target protein (6d5z, hemolysin II). The root-mean-square deviation, solvent-accessible surface area, the radius of gyration, root-mean-square fluctuations, and hydrogen bonds were used to ensure the binding stability of the docked complexes in the atomistic simulation and confirmed their stability. The combined effort of wet and dry lab-based work support, to some extent, that the antimicrobial properties of honey have great potential for application in medicine as well as in the food industries.


Subject(s)
Anti-Infective Agents , Honey , Anti-Bacterial Agents/analysis , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/analysis , Bacillus cereus , Furans , Hemolysin Proteins , Honey/analysis , Hydrogen Peroxide/pharmacology , Ligands , Microbial Sensitivity Tests , Proline , Pyrans , RNA , Solvents/analysis , Sugars , Water
19.
Molecules ; 27(19)2022 Sep 26.
Article in English | MEDLINE | ID: covidwho-2066274

ABSTRACT

New Ni (II) and Cu (II) complexes with pyridoxal-semicarbazone were synthesized and their structures were solved by X-ray crystallography. This analysis showed the bis-ligand octahedral structure of [Ni(PLSC-H)2]·H2O and the dimer octahedral structure of [Cu(PLSC)(SO4)(H2O)]2·2H2O. Hirshfeld surface analysis was employed to determine the most important intermolecular interactions in the crystallographic structures. The structures of both complexes were further examined using density functional theory and natural bond orbital analysis. The photocatalytic decomposition of methylene blue in the presence of both compounds was investigated. Both compounds were active toward E. coli and S. aureus, with a minimum inhibition concentration similar to that of chloramphenicol. The obtained complexes led to the formation of free radical species, as was demonstrated in an experiment with dichlorofluorescein-diacetate. It is postulated that this is the mechanistic pathway of the antibacterial and photocatalytic activities. Cyclic voltammograms of the compounds showed the peaks of the reduction of metal ions. A molecular docking study showed that the Ni(II) complex exhibited promising activity towards Janus kinase (JAK), as a potential therapy for inflammatory diseases, cancers, and immunologic disorders.


Subject(s)
Coordination Complexes , Semicarbazones , Anti-Bacterial Agents/pharmacology , Chloramphenicol , Coordination Complexes/chemistry , Crystallography, X-Ray , Escherichia coli/metabolism , Janus Kinases/metabolism , Ligands , Methylene Blue , Molecular Docking Simulation , Molecular Structure , Pyridoxal , Staphylococcus aureus/metabolism , Nickel , Copper
20.
Phytomedicine ; 107: 154481, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2061761

ABSTRACT

BACKGROUND: Traditional Chinese medicine (TCM), as a significant part of the global pharmaceutical science, the abundant molecular compounds it contains is a valuable potential source of designing and screening new drugs. However, due to the un-estimated quantity of the natural molecular compounds and diversity of the related problems drug discovery such as precise screening of molecular compounds or the evaluation of efficacy, physicochemical properties and pharmacokinetics, it is arduous for researchers to design or screen applicable compounds through old methods. With the rapid development of computer technology recently, especially artificial intelligence (AI), its innovation in the field of virtual screening contributes to an increasing efficiency and accuracy in the process of discovering new drugs. PURPOSE: This study systematically reviewed the application of computational approaches and artificial intelligence in drug virtual filtering and devising of TCM and presented the potential perspective of computer-aided TCM development. STUDY DESIGN: We made a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Then screening the most typical articles for our research. METHODS: The systematic review was performed by following the PRISMA guidelines. The databases PubMed, EMBASE, Web of Science, CNKI were used to search for publications that focused on computer-aided drug virtual screening and design in TCM. RESULT: Totally, 42 corresponding articles were included in literature reviewing. Aforementioned studies were of great significance to the treatment and cost control of many challenging diseases such as COVID-19, diabetes, Alzheimer's Disease (AD), etc. Computational approaches and AI were widely used in virtual screening in the process of TCM advancing, which include structure-based virtual screening (SBVS) and ligand-based virtual screening (LBVS). Besides, computational technologies were also extensively applied in absorption, distribution, metabolism, excretion and toxicity (ADMET) prediction of candidate drugs and new drug design in crucial course of drug discovery. CONCLUSIONS: The applications of computer and AI play an important role in the drug virtual screening and design in the field of TCM, with huge application prospects.


Subject(s)
COVID-19 , Medicine, Chinese Traditional , Artificial Intelligence , COVID-19/drug therapy , Drug Design , Humans , Ligands , Pharmaceutical Preparations
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