Structural insights into the effect of mutations in the spike protein of SARS-CoV-2 on the binding with human furin protein.

The SARS COV-2 and its variants are spreading around the world at an alarming speed, due to its higher transmissibility and the conformational changes caused by mutations. The resulting COVID-19 pandemic has imposed severe health consequences on human health. Several countries of the world including Pakistan have studied its genome extensively and provided productive findings. In the current study, the mCSM, DynaMut2, and I-Mutant servers were used to analyze the effect of identified mutations on the structural stability of spike protein however, the molecular docking and simulations approaches were used to evaluate the dynamics of the bonding network between the wild-type and mutant spike proteins with furin. We addressed the mutational modifications that have occurred in the spike protein of SARS-COV-2 that were found in 215 Pakistani's isolates of COVID-19 patients to study the influence of mutations on the stability of the protein and its interaction with the host cell. We found 7 single amino acid substitute mutations in various domains that reside in spike protein. The H49Y, N74K, G181V, and G446V were found in the S1 domain while the D614A, V622F, and Q677H mutations were found in the central helices of the spike protein. Based on the observation, G181V, G446V, D614A, and V622F mutants were found highly destabilizing and responsible for structural perturbation. Protein-protein docking and molecular simulation analysis with that of furin have predicted that all the mutants enhanced the binding efficiency however, the V622F mutant has greatly altered the binding capacity which is further verified by the KD value (7.1 E-14) and therefore may enhance the spike protein cleavage by Furin and increase the rate of infectivity by SARS-CoV-2. On the other hand, the total binding energy for each complex was calculated which revealed -50.57 kcal/mol for the wild type, for G181V -52.69 kcal/mol, for G446V -56.44 kcal/mol, for D614A -59.78 kcal/mol while for V622F the TBE was calculated to be -85.84 kcal/mol. Overall, the current finding shows that these mutations have increased the binding of Furin for spike protein and shows that D614A and V622F have significant effects on the binding and infectivity.

Structural insights into the effect of mutations in the spike protein of SARS-CoV-2 on the binding with human furin protein

The SARS COV-2 and its variants are spreading around the world at an alarming speed, due to its higher transmissibility and the conformational changes caused by mutations. The resulting COVID-19 pandemic has imposed severe health consequences on human health. Several countries of the world including Pakistan have studied its genome extensively and provided productive findings. In the current study, the mCSM, DynaMut2, and I-Mutant servers were used to analyze the effect of identified mutations on the structural stability of spike protein however, the molecular docking and simulations approaches were used to evaluate the dynamics of the bonding network between the wild-type and mutant spike proteins with furin. We addressed the mutational modifications that have occurred in the spike protein of SARS-COV-2 that were found in 215 Pakistani's isolates of COVID-19 patients to study the influence of mutations on the stability of the protein and its interaction with the host cell. We found 7 single amino acid substitute mutations in various domains that reside in spike protein. The H49Y, N74K, G181V, and G446V were found in the S1 domain while the D614A, V622F, and Q677H mutations were found in the central helices of the spike protein. Based on the observation, G181V, G446V, D614A, and V622F mutants were found highly destabilizing and responsible for structural perturbation. Protein-protein docking and molecular simulation analysis with that of furin have predicted that all the mutants enhanced the binding efficiency however, the V622F mutant has greatly altered the binding capacity which is further verified by the KD value (7.1 E−14) and therefore may enhance the spike protein cleavage by Furin and increase the rate of infectivity by SARS-CoV-2. On the other hand, the total binding energy for each complex was calculated which revealed −50.57 kcal/mol for the wild type, for G181V −52.69 kcal/mol, for G446V −56.44 kcal/mol, for D614A −59.78 kcal/mol while for V622F the TBE was calculated to be −85.84 kcal/mol. Overall, the current finding shows that these mutations have increased the binding of Furin for spike protein and shows that D614A and V622F have significant effects on the binding and infectivity.

Transient ST Segment Elevation in Two Patients with COVID-19 and a Normal Transthoracic Echocardiogram.

We continue to learn about cardiac involvement in patients with COVID-19. These patients can develop acute coronary syndrome and severe myocarditis with a reduced ejection fraction. We describe two critically ill COVID-19 patients who developed ST elevation that resolved on repeat ECG without any intervention. LEARNING POINT: ST elevation may occur in critically ill COVID-19 patients.

Syntheses and structural characterization of divalent metal complexes (Co, Ni, Pd and Zn) of sterically hindered thiourea ligand and a theoretical insight of their interaction with SARS-CoV-2 enzyme.

Reacting two equivalents of sterically hindered 1,3-bis(2,6-diethylphenyl)thiourea ligand (L) with CoCl2, NiBr2, PdX2 (X = Cl; Br) and ZnI2 in acetonitrile afforded the corresponding bulky thiourea ligand stabilized four coordinated monomeric [L2CoCl2] (1), [L2NiBr2] (2), [L2PdX2] (3a: X = Cl; 3b: X = Br) and [L2ZnI2] (4.2CH3CN) complexes. Compound 1, 2 and 4.2CH3CN are tetrahedral whereas Pd complexes (3a and 3b) are square planar. In solution, palladium complexes are dominated by cis-isomers. Structural characterization shows inter- and intramolecular hydrogen bonding. Hirshfeld surface and fingerprint plots indicated significant intermolecular interactions in the crystal network. Molecular docking analysis revealed relatively higher SARS-CoV-2 enzyme interacting abilities of the synthesized complexes compared to the free ligand. All compounds have been characterized by elemental analyses, NMR spectroscopy and single-crystal X-ray diffraction.

It's Your Turn, Are You Ready to Get Vaccinated? Towards an Exploration of Vaccine Hesitancy Using Sentiment Analysis of Instagram Posts

The deadly threat caused by the rapid spread of COVID-19 has been restricted by virtue of vaccines. However, there is misinformation regarding the certainty and positives outcome of getting vaccinated;hence, many people are reluctant to opt for it. Therefore, in this paper, we identified public sentiments and hesitancy toward the COVID-19 vaccines based on Instagram posts as part of intelligent surveillance. We first retrieved more than 10k publicly available comments and captions posted under different vaccine hashtags (namely, covaxin, covishield, and sputnik). Next, we translated the extracted comments into a common language (English), followed by the calculation of the polarity score of each comment, which helped identify the vaccine sentiments and opinions in the comments (positive, negative, and neutral) with an accuracy of more than 80%. Moreover, upon analysing the sentiments, we found that covaxin received 71.4% positive, 18.5% neutral, and 10.1% negative comments;covishield obtained 64.2% positive, 24.5% neutral, and 11.3% negative post;and sputnik received 55.8% positive, 15.5% neutral, and 28.7% negative sentiments. Understanding vaccination perceptions and views through Instagram comments, captions, and posts is helpful for public health officials seeking to enhance vaccine uptake by promoting positive marketing and reducing negative marketing. In addition to this, some interesting future directions are also suggested considering the investigated problem.

Synthesis, Characterization, Biological Activity and Molecular Docking Studies of Novel Organotin(IV) Carboxylates.

Four new carboxylates complexes with general formula R2SnL2 and R3SnL, where R = n-butyl (1, 3), methyl (2, 4) and L = 4-Chlorophenoxyacetate, were synthesized in significant yields. FT-IR analysis revealed a chelating (1 and 2) and a bridging bidentate (3 and 4) coordination modes for the carboxylate ligand in solid state which was further confirmed by the single crystal X-ray analysis of complex 4. The NMR data (1H, 13C and 119Sn) revealed a higher coordination number around the tin center in R2SnL2 (1 and 2) compared to R3SnL (3 and 4). A close matching was observed between the experimental and calculated structures (obtained at B3LYP/6-31G* + LANL2DZ basis set). Quantum chemical analysis indicates that the carboxylate moiety has the major contribution in the formation of filled and unfilled orbitals as well as in ligand to ligand intramolecular charge transfer during the electronic transitions. The cytotoxicity data of the screened compounds evaluated against lung cancer cell line (A549) and normal lung fibroblast cell line (MRC-5) revealed that 1, 3 and 4 have shown dose dependent cytotoxic effects while HL and 2 have shown steady and low cytotoxic activities. The antibacterial activity of complexes 1-4 is higher than that of HL. Molecular docking study showed an intercalation binding mode for complex 3 with DNA (docking score = -3.6005) involving four polar interactions. Complex 3 docking with tubulin (PDB ID 1SA0) with colchicine as a target protein resulted in three polar interactions (docking score -5.2957). Further, the docking analysis of the HL and 1-4 has shown an adequate interactions with the coronavirus SARS-CoV-2 spike protein, nucleocapsid protein and human angiotensin converting enzyme (ACE2).

Evaluation of Clinical Outcomes After Remdesivir Therapy in Patients with Moderately Severe Covid-19 Disease. Prospective Study (preprint)

Background Despite the fact that a number of therapeutic agents have been tested for the treatment of coronavirus disease 2019 (Covid-19), no antiviral agents have yet been proven to be effective.Objectives This study aims to evaluate the favorable clinical outcomes after remdesivir treatment in hospitalized patients with moderately severe COVID-19 disease in Pakistan.Methods A prospective study in hospitalized patients with moderately severe Covid-19 disease was conducted between January 2021- October 2021. The patients were divided into remdesivir-treated and control groups. The Remdesivir-treated group received 200mg IV, followed by 100mg once daily for four days. In addition to standard care, all patients received corticosteroid therapy. The clinical status of remdesivir patients was assessed after the 5th day of treatment, including proportion negative polymerase chain reaction test for COVID-19, length of hospitalization, improvement in oxygen demand, and effects on C-reactive protein (CRP) levels. Multivariate analysis and paired sample T-test were performed to evaluate a favorable response to remdesivir treatment and results were compared with a control group.Result In total, 328 patients were enrolled in the study, with 162 of them receiving IV remdesivir on the day of admission. The C-reactive protein level in the remdesivir treated group [median 22.0 (14.0–36.7)] was significantly lower (p < 0.001) than in the remdesivir naive group [median 79.1 (57.4–139.0)]. The number of days spent in the hospital was significantly different between the remdesivir-treated and remdesivir-naive groups [6.2 0.5] (p < 0.001). In the remdesivir-treated group, 36.7% of patients were discharged with a negative PCR, compared to 21.6% in the control group (p < 0.001). In comparison to the control group, the remdesivir treated group showed a significant improvement in the ratio of arterial oxygen partial pressure to fractional inspired oxygen (p < 0.001).Conclusion The remdesivir treatment was found to be superior to improve clinical outcomes among moderately severe Covid-19 disease patients.

Synthesis, characterization, antioxidant, antileishmanial, anticancer, DNA and theoretical SARS-CoV-2 interaction studies of copper(II) carboxylate complexes.

Copper(II) carboxylate complexes [Cu2(OOCR)4L2] (1) and [Cu2(OOCR`)4OCO(R`)CuL2]n (2), where L = 2-methyl pyridine, R = 2-chlorophenyl acetate and R` = 2-fluorophenyl acetate were synthesized and characterized by FT-IR spectroscopy and single crystal X-ray analysis. Complex 1 exhibits the typical paddlewheel array of a dinuclear copper(II) complex with carboxylate ligands. In complex 2, this scaffold is further extended into a polymeric arrangement based on alternate paddlewheel and square planar moieties with distinct coordination spheres. The complexes showed better 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl radical scavenging activities and have been found to be more potent antileishmanial agents than their corresponding free ligand acid species. UV-Vis absorption titrations revealed good DNA binding abilities {Kb = 9.8 × 104 M-1 (1) and 9.9 × 104 M-1 (2)} implying partial intercalation of the complexes into DNA base pairs along with groove binding. The complexes displayed in vitro cytotoxic activity against malignant glioma U-87 (MG U87) cell lines. Computational docking studies further support complex-DNA binding by intercalation. Molecular docking investigations revealed probable interactions of the complexes with spike protein, the nucleocapsid protein of SARS-CoV-2 and with the angiotensin converting enzyme of human cells.

Syntheses, crystal structures, antioxidant, in silico DNA and SARS-CoV-2 interaction studies of triorganotin(IV) carboxylates

Triorganotin(IV) carboxylate complexes R3SnL, where R = C4H9 (1), CH3 (2) and L = 2-chlorophenyl ethanoate, were synthesized and characterized by elemental analysis, FT-IR, NMR (1H, 13C, 119Sn) and X-ray single crystal analysis. The solid state analyses confirmed a bridging bidentate coordination mode for the carboxylate ligand rendering the tin ion a penta-coordinated centre in the synthesized complexes. NMR spectra revealed a change in the coordination number (5→4) for tin when in the solution. The structural geometry and the electronic properties of complexes were calculated by using the density functional theory (DFT) method at B3LYP level 6-31G(d, p) and Lanl2DZ basis sets. A fairly good agreement was found between the observed and theoretical bond length and bond angle values for the complex (1) and (2). The in vitro antioxidant potential of the complexes was investigated by DPPH, ferrous ion chelation, ferric ion reducing, total antioxidant and hydroxyl free radical scavenging assays. The nature of the tin bonded R groups has apparently a significant impact on the antioxidant activity of the complexes. Molecular docking studies suggest intercalation as possible mode of complex-DNA interactions. Docking studies also confirm that interactions of the two complexes with some active site residues of SARS-CoV-2 nucleocapsid protein and angiotensin-converting enzyme 2 (ACE2) are probable.