Computational profiling of natural compounds as promising inhibitors against the spike proteins of SARS-CoV-2 wild-type and the variants of concern, viral cell-entry process, and cytokine storm in COVID-19.

The continuous spread and evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the rapid surge in infection cases in the coronavirus disease 2019 (COVID-19) evoke a dire need for effective therapeutics. In this study, we explored the inhibitory potential of a library of 605 phytocompounds, selected from Indian medicinal plants with reported antiviral and anti-inflammatory activities, against the receptor-binding domain of spike proteins of the SARS-CoV-2 wild-type and the variants of concern, including variants B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Our approach was based on extensive molecular docking, assessment of drug-likeness, and robust molecular dynamics simulations. We also identified promising inhibitory candidates against the host (human) proteins associated with SARS-CoV-2 spike activation and attachment, namely, ACE2 receptor, proteases TMPRSS2 and CTSL, and the endocytic regulator AAK1. In addition, we screened promising inhibitory compounds against the human proinflammatory cytokines- IL-6, IL-1ß, TNF-α, and IFN-γ, that are associated with the adverse cytokine storm in COVID-19 patients. Our analysis returned an encouraging list of promising inhibitory candidates that includes: abietatriene against the spike proteins of the SARS-CoV-2 wild-type and the variants of concern; taraxerol against the human ACE2, CTSL and TNF-α; ß-amyrin against the human TMPRSS2; cynaroside against the human AAK1 and IL-1ß; and friedelin against the human IL-6 and IFN-γ. Our findings provide substantial evidence for the inhibitory potential of these compounds and encourage further in vitro and in vivo studies to validate their use as safe and effective therapeutics against COVID-19.

Anisotine and amarogentin as promising inhibitory candidates against SARS-CoV-2 proteins: a computational investigation.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents an unprecedented challenge to global public health with researchers striving to find a possible therapeutic candidate that could limit the spread of the virus. In this context, the present study employed an in silico molecular interaction-based approach to estimate the inhibitory potential of the phytochemicals from ethnomedicinally relevant Indian plants including Justicia adhatoda, Ocimum sanctum and Swertia chirata, with reported antiviral activities against crucial SARS-CoV-2 proteins. SARS-CoV-2 proteins associated with host attachment and viral replication namely, spike protein, main protease enzyme Mpro and RNA-dependent RNA polymerase (RdRp) are promising druggable targets for COVID-19 therapeutic research. Extensive molecular docking of the phytocompounds at the binding pockets of the viral proteins revealed their promising inhibitory potential. Subsequent assessment of physicochemical features and potential toxicity of the compounds followed by robust molecular dynamics simulations and analysis of MM-PBSA energy scoring function revealed anisotine against SARS-CoV-2 spike and Mpro proteins and amarogentin against SARS-CoV-2 RdRp as potential inhibitors. It was interesting to note that these compounds displayed significantly higher binding energy scores against the respective SARS-CoV-2 proteins compared to the relevant drugs that are currently being targeted against them. Present research findings confer scopes to explore further the potential of these compounds in vitro and in vivo towards deployment as efficient SARS-CoV-2 inhibitors and development of novel effective therapeutics.Communicated by Ramaswamy H. Sarma.

Structural Insight into the Binding of Cyanovirin-N with the Spike Glycoprotein, Mpro and PLpro of SARS-CoV-2: Protein-Protein Interactions, Dynamics Simulations and Free Energy Calculations.

The emergence of COVID-19 continues to pose severe threats to global public health. The pandemic has infected over 171 million people and claimed more than 3.5 million lives to date. We investigated the binding potential of antiviral cyanobacterial proteins including cyanovirin-N, scytovirin and phycocyanin with fundamental proteins involved in attachment and replication of SARS-CoV-2. Cyanovirin-N displayed the highest binding energy scores (-16.8 ± 0.02 kcal/mol, -12.3 ± 0.03 kcal/mol and -13.4 ± 0.02 kcal/mol, respectively) with the spike protein, the main protease (Mpro) and the papainlike protease (PLpro) of SARS-CoV-2. Cyanovirin-N was observed to interact with the crucial residues involved in the attachment of the human ACE2 receptor. Analysis of the binding affinities calculated employing the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) approach revealed that all forms of energy, except the polar solvation energy, favourably contributed to the interactions of cyanovirin-N with the viral proteins. With particular emphasis on cyanovirin-N, the current work presents evidence for the potential inhibition of SARS-CoV-2 by cyanobacterial proteins, and offers the opportunity for in vitro and in vivo experiments to deploy the cyanobacterial proteins as valuable therapeutics against COVID-19.

Cyanobacterial metabolites as promising drug leads against the Mpro and PLpro of SARS-CoV-2: an in silico analysis.

A novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has emerged as the causative agent behind the coronavirus disease 2019 (COVID-19) pandemic. Treatment efforts have been severely impeded due to the lack of specific effective antiviral drugs for the treatment of COVID-associated pathologies. In the present research endeavour the inhibitory prospects of cyanobacterial metabolites were assessed at the active binding pockets of the two vital SARS-CoV-2 proteases namely, main protease (Mpro) and the papain-like protease (PLpro) that proteolytically process viral polyproteins and facilitate viral replication, employing an in silico molecular interaction-based approach. It was evident from our analysis based on the binding energy scores that the metabolites cylindrospermopsin, deoxycylindrospermopsin, carrageenan, cryptophycin 52, eucapsitrione, tjipanazole, tolyporphin and apratoxin A exhibited promising inhibitory potential against the SARS-CoV-2 Mpro. The compounds cryptophycin 1, cryptophycin 52 and deoxycylindrospermopsin were observed to display encouraging binding energy scores with the PLpro of SARS-CoV-2. Subsequent estimation of physicochemical properties and potential toxicity of the metabolites followed by robust molecular dynamics simulations and analysis of MM-PBSA energy scoring function established deoxycylindrospermopsin as the most promising inhibitory candidate against both SARS-CoV-2 proteases. Present research findings bestow ample scopes to further exploit the potential of deoxycylindrospermopsin as a successful inhibitor of SARS-CoV-2 in vitro and in vivo and pave the foundation for the development of novel effective therapeutics against COVID-19.Communicated by Ramaswamy H. Sarma.

Monitoring the acclimatization of a Chlorella sp. From freshwater to hypersalinity using photosynthetic parameters of pulse amplitude modulated fluorometry.

Contamination of freshwater raceway ponds impedes the commercial cultivation of microalgae. Acclimatization of freshwater microalgae to hypersaline conditions offers a means to reduce contamination. A freshwater Chlorella species was cultured in a gradient of salinities ranging from 5 to 40‰ and pulse amplitude modulated fluorometry recorded photosynthetic functioning. While the average salinity of seawater is 35‰, optimum acclimatization occurred at 20‰, at which point the growth rate (1.6 µg chl a L-1d-1) was not significantly different from the control (1.8 µg chl a L-1d-1). The maximum relative electron transfer rate was lower (9 to 12 µmol m-2s-1) at 5 to 20‰ as compared to 40‰ (28 µmol m-2s-1) where no algal growth was recorded. ATP and NADPH were thus shunted towards synthesis of molecules that offset cytoplasmic osmotic stress. Culturing this Chlorella strain in raceway ponds under saline conditions may reduce contamination and improve productivity.

Photosystem I fluorescence as a physiological indicator of hydrogen production in Chlamydomonas reinhardtii.

This study investigated the interrelations between hydrogen synthesis and Photosystem I electron transport rate in Chlamydomonas reinhardtii. The fluorescence of both photosystems (PS I and PS II) was monitored using a Dual Pulse Amplitude Modulated (PAM) Fluorometer. Hydrogen synthesis was induced by eliminating sulphur from the growth media (TAP-S). Multiple physiological parameters [rETR, Y (I), Y (II), NPQ, α, Fv/Fm and YI:YII] were recorded using the Dual PAM and correlated to hydrogen produced. There was a 66% increase in Photosystem I rETRmax during hydrogen production. A significant direct correlation existed between PS 1 rETRmax and hydrogen evolution values over the ten-day period (r = 0.895, p < 0.01) indicating that PS I can be considered as a driver of H2 production. Significant correlations between rETRmax of PS I and H2 evolution suggest a novel physiological indicator to monitor H2 production during the three critical phases identified in this study.

Robust photosystem I activity by Cyanothece sp. (Cyanobacteria) and its role in prolonged bloom persistence in lake St Lucia, South Africa.

Worldwide, cyanobacterial blooms are becoming more frequent, exacerbated by eutrophication, anthropogenic effects, and global climate change. Environmental factors play a direct role in photosynthesis of cyanobacteria and subsequent cellular changes, growth, and bloom dynamics. This study investigated the photosynthetic functioning of a persistent bloom-forming (18 months) cyanobacterium, Cyanothece sp., isolated from Lake St Lucia, South Africa. DUAL-PAM fluorometric methods were used to observe physiological responses in Cyanothece sp. photosystems I and II. Results show that photosystem I activity was maintained under all environmental conditions tested, while photosystem II activity was not observed at all. Out of the environmental factors tested (temperature, salinity, and nitrogen presence), only temperature significantly influenced photosystem I activity. In particular, high temperature (40 °C) facilitated faster electron transport rates, while effects of salinity and nitrogen were variable. Cyanothece sp. has shown to sustain bloom status for long periods largely because of the essential role of photosystem I activity during highly dynamic and even extreme (e.g., salinities higher than 200) environmental conditions. This ensures the continual supply of cellular energy (e.g. ATP) to important processes such as nitrogen assimilation, which is essential for protein synthesis, cell growth and, therefore, bloom maintenance.