Resveratrol and Its Natural Analogues Inhibit RNA Dependant RNA Polymerase (RdRp) of Rhizopus oryzae in Mucormycosis through Computational Investigations

Mucormycosis (or black fungus infection) is a life-threatening, but rare fungal infection with predominant occurrence in immunosuppressed patients following the SARS-CoV-2 infection. Rhizopus oryzae (R. O.) causes about 70% of all cases of mucormycosis. RNA dependent RNA polymerase (RdRp) is a key fungal protein implicated in the genome replication and multiplication of R. oryzae. In view of biological significance of resveratrol (RES), rich in grape skin extract, on various microbial infections and inflammatory diseases including gum infections and periodontitis, our present study was aimed at in silico investigation of RES and its two natural analogues, piceatannol (3,5,3',4'-tetrahydroxy-trans-stilbene, PIC), and 3,5,4'-trimethoxy-trans-stilbene (TMS) for their development as successful antifungal agents targeting the R. O. specific RdRp to combat the deadly mucormycosis. Due to the unavailability of the three-dimensional structure of R. O. RdRp in the Protein Database Bank (PDB), the protein structure of RdRp was modeled using the target sequence of RT/Duplex (Set-Met) (PDB ID: 6AR3, 3.41 Å) by homology modeling. Using the modeled structure of R. O. RdRp, docking and molecular dynamics (MD) simulation studies were carried out in Schrödinger suite version 2021-2 software. The findings of docking, MD simulations and MM-PBSA binding energies conclude that the RES, PIC and TMS possess predictable and stable binding affinity/interactions to the R. O. RdRp. These bioactive compounds could potentially inhibit the activity of R. O. RdRp. Further, density function theory (DFT) analysis (B3LYP, 6-311 G* basis set) was performed, and results of DFT analysis indicate that the compound PIC could be a more potential inhibitor for R. O. RdRp over RES. In in silico drug-likeness and ADMET prediction studies, all of the compounds exhibited acceptable drug-likeness, the Lipinski’s rule of five and pharmacokinetic parameters. Finally, it can be concluded that RES and its two natural analogues, PIC and TMS are the potential inhibitors of R. O. RdRp based on docking, MD and DFT studies. [ FROM AUTHOR] Copyright of Polycyclic Aromatic Compounds is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Probing the competitive inhibitor efficacy of frog-skin alpha helical AMPs identified against ACE2 binding to SARS-CoV-2 S1 spike protein as therapeutic scaffold to prevent COVID-19.

In COVID-19 infection, the SARS-CoV-2 spike protein S1 interacts to the ACE2 receptor of human host, instigating the viral infection. To examine the competitive inhibitor efficacy of broad spectrum alpha helical AMPs extracted from frog skin, a comparative study of intermolecular interactions between viral S1 and AMPs was performed relative to S1-ACE2p interactions. The ACE2 binding region with S1 was extracted as ACE2p from the complex for ease of computation. Surprisingly, the Spike-Dermaseptin-S9 complex had more intermolecular interactions than the other peptide complexes and importantly, the S1-ACE2p complex. We observed how atomic displacements in docked complexes impacted structural integrity of a receptor-binding domain in S1 through conformational sampling analysis. Notably, this geometry-based sampling approach confers the robust interactions that endure in S1-Dermaseptin-S9 complex, demonstrating its conformational transition. Additionally, QM calculations revealed that the global hardness to resist chemical perturbations was found more in Dermaseptin-S9 compared to ACE2p. Moreover, the conventional MD through PCA and the torsional angle analyses indicated that Dermaseptin-S9 altered the conformations of S1 considerably. Our analysis further revealed the high structural stability of S1-Dermaseptin-S9 complex and particularly, the trajectory analysis of the secondary structural elements established the alpha helical conformations to be retained in S1-Dermaseptin-S9 complex, as substantiated by SMD results. In conclusion, the functional dynamics proved to be significant for viral Spike S1 and Dermaseptin-S9 peptide when compared to ACE2p complex. Hence, Dermaseptin-S9 peptide inhibitor could be a strong candidate for therapeutic scaffold to prevent infection of SARS-CoV-2.

Identification of bioactive molecules from Triphala (Ayurvedic herbal formulation) as potential inhibitors of SARS-CoV-2 main protease (Mpro) through computational investigations.

Severe acute respiratory syndrome coronavirus disease (SARS-CoV-2) induced coronavirus disease 2019 (COVID-19) pandemic is the present worldwide health emergency. The global scientific community faces a significant challenge in developing targeted therapies to combat the SARS-CoV-2 infection. Computational approaches have been critical for identifying potential SARS-CoV-2 inhibitors in the face of limited resources and in this time of crisis. Main protease (Mpro) is an intriguing drug target because it processes the polyproteins required for SARS-CoV-2 replication. The application of Ayurvedic knowledge from traditional Indian systems of medicine may be a promising strategy to develop potential inhibitor for different target proteins of SARS-CoV-2. With this endeavor, we docked bioactive molecules from Triphala, an Ayurvedic formulation, against Mpro followed by molecular dynamics (MD) simulation (100 ns) to investigate their inhibitory potential against SARS-CoV-2. The top four best docked molecules (terflavin A, chebulagic acid, chebulinic acid, and corilagin) were selected for MD simulation study and the results obtained were compared to native ligand X77. From docking and MD simulation studies, the selected molecules showed promising binding affinity with the formation of stable complexes at the active binding pocket of Mpro and exhibited negative binding energy during MM-PBSA calculations, indication their strong binding affinity with the target protein. The identified bioactive molecules were further analyzed for drug-likeness by Lipinski's filter, ADMET and toxicity studies. Computational (in silico) investigations identified terflavin A, chebulagic acid, chebulinic acid, and corilagin from Triphala formulation as promising inhibitors of SARS-CoV-2 Mpro, suggesting experimental (in vitro/in vivo) studies to further explore their inhibitory mechanisms.

Determinants of severity among hospitalised COVID-19 patients: Hospital-based case-control study, India, 2020.

BACKGROUND: Risk factors for the development of severe COVID-19 disease and death have been widely reported across several studies. Knowledge about the determinants of severe disease and mortality in the Indian context can guide early clinical management. METHODS: We conducted a hospital-based case control study across nine sites in India to identify the determinants of severe and critical COVID-19 disease. FINDINGS: We identified age above 60 years, duration before admission >5 days, chronic kidney disease, leucocytosis, prothrombin time > 14 sec, serum ferritin >250 ng/mL, d-dimer >0.5 ng/mL, pro-calcitonin >0.15 µg/L, fibrin degradation products >5 µg/mL, C-reactive protein >5 mg/L, lactate dehydrogenase >150 U/L, interleukin-6 >25 pg/mL, NLR ≥3, and deranged liver function, renal function and serum electrolytes as significant factors associated with severe COVID-19 disease. INTERPRETATION: We have identified a set of parameters that can help in characterising severe COVID-19 cases in India. These parameters are part of routinely available investigations within Indian hospital settings, both public and private. Study findings have the potential to inform clinical management protocols and identify patients at high risk of severe outcomes at an early stage.

Repurposing of phytomedicine-derived bioactive compounds with promising anti-SARS-CoV-2 potential: Molecular docking, MD simulation and drug-likeness/ADMET studies.

In view of the potential of traditional plant-based remedies (or phytomedicines) in the management of COVID-19, the present investigation was aimed at finding novel anti-SARS-CoV-2 molecules by in silico screening of bioactive phytochemicals (database) using computational methods and drug repurposing approach. A total of 160 compounds belonging to various phytochemical classes (flavonoids, limonoids, saponins, triterpenoids, steroids etc.) were selected (as initial hits) and screened against three specific therapeutic targets (Mpro/3CLpro, PLpro and RdRp) of SARS-CoV-2 by docking, molecular dynamics simulation and drug-likeness/ADMET studies. From our studies, six phytochemicals were identified as notable ant-SARS-CoV-2 agents (best hit molecules) with promising inhibitory effects effective against protease (Mpro and PLpro) and polymerase (RdRp) enzymes. These compounds are namely, ginsenoside Rg2, saikosaponin A, somniferine, betulinic acid, soyasapogenol C and azadirachtin A. On the basis of binding modes and dynamics studies of protein-ligand intercations, ginsenoside Rg2, saikosaponin A, somniferine were found to be the most potent (in silico) inhibitors potentially active against Mpro, PLpro and RdRp, respectively. The present investigation can be directed towards further experimental studies in order to confirm the anti-SARS-CoV-2 efficacy along with toxicities of identified phytomolecules.

Strategies for antigen testing: An alternative approach to widespread PCR testing (preprint)

Multiple applications of low cost and rapid antigen tests for individuals, in parallel (at the same time) or at times sufficiently close to each other, when appropriately interpreted can considerably increase sensitivity of these tests, improving on their performance greatly. Under reasonable assumptions, this occurs when considering a positive to arise in a composite test if at least one of two underlying repeated tests are positive. Parallel Rapid Testing can potentially provide a form of testing that is accessible (combining wide availability and lack of expense) and quick. Moreover, it can provide a level of sensitivity that is comparable to seemingly more sophisticated but more expensive alternatives. In combination with sequential testing, this strategy offers an alternative method of testing that can be applied immediately and on a widespread basis.

Utilization of COVID-19 Treatments and Clinical Outcomes among Patients with Cancer: A COVID-19 and Cancer Consortium (CCC19) Cohort Study.

Among 2,186 U.S. adults with invasive cancer and laboratory-confirmed SARS-CoV-2 infection, we examined the association of COVID-19 treatments with 30-day all-cause mortality and factors associated with treatment. Logistic regression with multiple adjustments (e.g., comorbidities, cancer status, baseline COVID-19 severity) was performed. Hydroxychloroquine with any other drug was associated with increased mortality versus treatment with any COVID-19 treatment other than hydroxychloroquine or untreated controls; this association was not present with hydroxychloroquine alone. Remdesivir had numerically reduced mortality versus untreated controls that did not reach statistical significance. Baseline COVID-19 severity was strongly associated with receipt of any treatment. Black patients were approximately half as likely to receive remdesivir as white patients. Although observational studies can be limited by potential unmeasured confounding, our findings add to the emerging understanding of patterns of care for patients with cancer and COVID-19 and support evaluation of emerging treatments through inclusive prospective controlled trials. SIGNIFICANCE: Evaluating the potential role of COVID-19 treatments in patients with cancer in a large observational study, there was no statistically significant 30-day all-cause mortality benefit with hydroxychloroquine or high-dose corticosteroids alone or in combination; remdesivir showed potential benefit. Treatment receipt reflects clinical decision-making and suggests disparities in medication access.This article is highlighted in the In This Issue feature, p. 1426.

Population health, economics and ethics in the age of COVID-19.

Are the steps that have been taken to arrest the spread of COVID-19 justifiable? Specifically, are they likely to have improved public health understood according to widely used aggregate population health measures, such as Quality Adjusted Life Years (QALYs) and Disability Adjusted Life Years (DALYs) as much or more than alternatives? This is a reasonable question, since such measures have been promoted extensively in global and national health policy by influential actors, and they have become almost synonymous with quantification of public health. If the steps taken against COVID-19 did not meet this test, then either the measures or the policies must be re-evaluated. There are indications that policies against COVID-19 may have been unbalanced and therefore not optimal. A balanced approach to protecting population health should be proportionate in its effects across distinct health concerns at a moment, across populations over time and across populations over space. These criteria provide a guide to designing and implementing policies that diminish harm from COVID-19 while also providing due attention to other threats to aggregate population health. They should shape future policies in response to this pandemic and others.