Dengue virus (DENV) infections are rampant in tropical and subtropical regions of the world with millions of people at risk. There is still no specific antiviral treatment available against these infections. Amongst the different potential therapeutic targets, DENV protease is considered an important target because of its crucial role in the viral replication cycle. We are reporting here a potent DENV protease inhibitor, eugeniin (3), which has been isolated from cloves, along with two other weaker inhibitors, isobiflorin (1) and biflorin (2). In this study, the IC 50 values of 3 against the proteases of DENV serotype-2 and -3 were found to be 94.7 nM and 7.5 μM, respectively. Mechanistically, the compounds 1−3 exhibited a competitive type of inhibition, which were further substantiated by computational docking and saturation transfer difference (STD) NMR spectroscopy. Atomic-level details of the binding of these molecules at the active site of the protease suggested extensive interactions mediated by a network of hydrogen bonds and hydrophobic contacts. With further evaluation, these inhibitors are highly promising in the context of antiviral therapeutics development against DENV.
The COVID-19 pandemic has claimed more than a million lives worldwide within a short time span. Due to the unavailability of specific antiviral drugs or vaccine, the infections are causing panic both in general public and among healthcare providers. Therefore, an urgent discovery and development of effective antiviral drug for the treatment of COVID-19 is highly desired. Targeting the main protease (M pro) of the causative agent, SARS-CoV-2 has great potential for drug discovery and drug repurposing efforts. Published crystal structures of SARS-CoV-2 M pro further facilitated in silico investigations for discovering new inhibitors against M pro. The present study aimed to screen several libraries of synthetic flavonoids and benzisothiazolinones as potential SARS-CoV-2 M pro inhibitors using in silico methods. The short-listed compounds after virtual screening were filtered through SwissADME modeling tool to remove molecules with unfavorable pharmacokinetics and medicinal properties. The drug-like molecules were further subjected to iterative docking for the identification of top binders of SARS-CoV-2 M pro. Finally, molecular dynamic (MD) simulations and binding free energy calculations were performed for the evaluation of the dynamic behavior, stability of protein-ligand complex, and binding affinity, resulting in the identification of thioflavonol, TF-9 as a potential inhibitor of M pro. The computational studies further revealed the binding of TF-9 close to catalytic dyad and interactions with conserved residues in the S1 subsite of the substrate binding site. Our in-silico study demonstrated that synthetic analogs of flavonoids, particularly thioflavonols, have a strong tendency to inhibit the main protease M pro , and thereby inhibit the reproduction of SARS-CoV-2.
Several new N-substituted 1,2-benzisothiazol-3(2H)-ones (BITs) were synthesised through a facile synthetic route for testing their anti-dengue protease inhibition. Contrary to the conventional multistep synthesis, we achieved structurally diverse BITs with excellent yields using a two-step, one-pot reaction strategy. All the synthesised compounds were prescreened for drug-like properties using the online Swiss Absorption, Distribution, Metabolism and Elimination (SwissADME) model, indicating their favourable pharmaceutical properties. Thus, the synthesised BITs were tested for inhibitory activity against the recombinant dengue virus serotype-2 (DENV-2) NS2BNS3 protease. Dose–response experiments and computational docking analyses revealed that several BITs bind to the protease in the vicinity of the catalytic triad with IC50 values in the micromolar range. The DENV2 infection assay showed that two BITs, 2-(2-chlorophenyl)benzo[d]isothiazol-3(2H)-one and 2-(2,6-dichlorophenyl)benzo[d]isothiazol-3(2H)-one, could suppress DENV replication and virus infectivity. These results indicate the potential of BITs for developing new anti-dengue therapeutics.
Using a simple and inexpensive sol-gel synthesis technique, Nd and Cd doped copper chromite spinel nanoparticles (MxCu1-xCr2O4) with x=0.2, 0.4, 0.6, and 0.8 were investigated. The crystal structure, elemental composition, nanoparticles nature, and bandgap of the synthesized nanoparticles were determined using XRD, EDS, SEM, Raman spectroscopy, and Photoluminescence. As prepared calcined at 750°C for four hours, resulting in an increase in average grain size from 37nm to 41nm, as demonstrated by XRD results. XRD tells us about the crystal size and dislocation density of samples. The value of 2???? for the XRD patterns is ranging from 25 to 55 . The band gap is calculated from the PL spectra and is 4.96 eV for the parent compound. When we doped elements with different concentrations in parent compound, the value of band gap decreases to 2.43 eV for Neodymium and 2.42eV for Cadmium. Similarly, SEM results show that the structure of pure copper chromites is tetragonal, and that after doping with other compounds, the structure will change according to the characteristics of Nano particles. In the PL spectra, four peaks are obtained: one at 347nm, one at 380nm, one at 500nm, and one at 600nm.EDS demonstrated that Cadmium and Neodymium was successfully doped in copper chromite and completely merged
Background: The trigger points are hyperirritable spots found usually in the muscle fascia or within the taut bands of skeletal muscles that is painful on compression. Ischemic compression technique uses the application of sustained pressure with sufficient force and for long enough so as to slow down the flow of blood and releasing tension out of the muscle. Strain counterstrain (SCS), also known as positional release, is a passive positional treatment that relieves musculoskeletal pain and dysfunction by indirect hand manipulation. Objectives: The aim of this study was to compare the effects of ischemic compression technique and strain counterstrain technique on pain, neck lateral flexion and disability in patients with upper trapezius trigger points. Methodology: The RCT was conducted on 36 male and female participants aging 25-45 having maximum of 5 trigger points in the upper trapezius bilaterally. The patients were divided equally to ischemic compression and strain counterstrain group by lottery method. The treatment was given for 3 days a week for 4 weeks. The NPRS, NDI and cervical lateral flexion were used as outcome measure. The assessment of the outcome measures was done on baseline, after 2nd week and after 4th week. The data was analyzed by SPSS version 26 using appropriate tests depending upon the normality by keeping the level of significance at 0.05. Results: Out of 36 participants (Mean age 32.96 ± 5.91), 20 were male and 16 were female, 3 participants lost to follow up. The within group analysis of NPRS and NDI done by Friedman test and that of cervical flexion done by repeated measures ANOVA showed that the both the interventions has produced significant (p<0.05) effects on pain, neck disability and range of motion, but the between group analysis of NPRS and NDI done by Mann-Whitney test and that of Cervical ROM done by Independent samples t-test showed that none of the two technique produced significant results (p>0.05) as compared to the other in subjects with upper trapezius trigger points. Conclusion: A 4-week intervention of the ischemic compression and strain counterstrain produced significant results in reducing the intensity of pain, the cervical disability and improving the cervical range of motion, but the intergroup comparison showed that both the ischemic compression and strain counterstrain were equally effective and none of them produced significant results as compared to others on patients with upper trapezius trigger points. Keywords: Ischemic Compression Technique; Strain Counterstrain; Upper Trapezius Trigger Points.
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