In-silico studies on wild orange (Citrus macroptera Mont.) compounds against COVID-19 pro-inflammation targets.

One-fifth of COVID-19 patients suffer a severe course of COVID-19 (SARS-CoV-2) infection; however, the specific causes remain unclear. Despite numerous papers that have been flooded in different scientific journals clear clinical picture of COVID-19 aftermath persists to remain fuzzy. The survivors of severe COVID-19infection having defeated the virus are just the starting of an uncharted recovery path. Currently, there is no drug available that is safe to consume to combat this pandemic. However, researchers still struggling to find specific therapeutic solutions. The present study employed an in silico approach to assessing the inhibitory potential of the phytochemicals obtained from GC-MS analysis of Citrus macroptera against inflammatory proteins like COX-2, NMDAR and VCAM-1 which remains in a hyperactive state even after a patient is fully cured of this deadly mRNA virus. An extensive molecular docking investigation of the phyto-compounds at the active binding pockets of the inflammatory proteins revealed the promising inhibitory potential of the phytochemicals. Reasonable physicochemical attributes of the compounds following Lipinski's rule of five, VEBER and PAINS analysis further established them as potential therapeutic candidates against aforesaid inflammatory proteins. MM-GBSA binding free energy estimation revealed that Limonene was the most promising candidate displaying the highest binding efficacy with the concerned VCAM-1 protein included in the present analysis. An interesting finding is the phytochemicals exhibited better binding energy scores with the concerned COX-2, VCAM-1 and NMDA receptor proteins than the conventional drugs that are specifically targeted against them. Our in silico results suggest that all the natural phyto-compounds derived from C. macroptera could be employed in Post covid inflammation complexities after appropriate pre-clinical and clinical trials for further scientific validation.Communicated by Ramaswamy H. Sarma.

Neem and Turmeric in the management of Covid Associated Mucormycosis (CAM) derived through network pharmacology.

Mucormycosis or 'Black Fungus' has been known to target immunocompromised individuals even before the emergence of COVID-19. Nevertheless, the present circumstances provide the best opening for Covid Associated Mucormycosis (CAM), as the global pandemic is engulfing a large part of human population making them immunocompromised. This drastic increase in Mucormycosis infections has to be addressed as early as possible. There is a growing tendency of relying upon herbal drugs that have minimal side effects and does not compromise our immune system. Recently, the concept of network pharmacology has grabbed the attention of modern science, especially advanced medical sciences. This is a new discipline that can use computational power to systematically catalogue the molecular interactions between botanical formulations and the human body. In this study, Neem and Turmeric was considered as the target plants and an attempt was made to reveal various aspects through which phytocompounds derived from them may effectively manage CAM menace. We have taken a step-by-step approach for identifying the target proteins and ligands associated with Mucormycosis treatment. Functional network analysis and Molecular docking approaches were applied to validate our findings. Quercetin derived from both Neem and Turmeric was found to be one of the main phytocompounds working against Mucormycosis. Along with that, Caffeic acid, Curcumin, Kaempferol, Tetrahydrocurcumin and Myricetin also play a pivotal role in fighting against Black-Fungus. A thorough analysis of our result suggested a triple-front attack on the fungal pathogens and the approaches are necrosis inhibition, iron chelation and immuno-boosting.Communicated by Ramaswamy H. Sarma.

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.

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.

In silico inquest reveals the efficacy of Cannabis in the treatment of post-Covid-19 related neurodegeneration.

Coronavirus (SARS-CoV-2), the causative agent of the Covid-19 pandemic has proved itself as the deadliest pathogen. A major portion of the population has become susceptible to this strain. Scientists are pushing their limits to formulate a vaccine against Covid-19 with the least side effects. Although the recent discoveries of vaccines have shown some relief from the covid infection rate, however, physical fatigue, mental abnormalities, inflammation and other multiple organ damages are arising as post-Covid symptoms. The long-term effects of these symptoms are massive. Patients with such symptoms are known as long-haulers and treatment strategy against this condition is still unknown. In this study, we tried to explore a strategy to deal with the post-Covid symptoms. We targeted three human proteins namely ACE2, Interleukin-6, Transmembrane serine protease and NRP1 which are already reported to be damaged via Covid-19 proteins and upregulated in the post-Covid stage. Our target plant in this study is Cannabis (popularly known as 'Ganja' in India). The molecular docking and simulation studies revealed that Cannabidiol (CBD) and Cannabivarin (CVN) obtained from Cannabis can bind to post-Covid symptoms related central nervous system (CNS) proteins and downregulate them which can be beneficial in post-covid symptoms treatment strategy. Thus we propose Cannabis as an important therapeutic plant against post-Covid symptoms.Communicated by Ramaswamy H. Sarma.

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.

In silico screening predicts common cold drug Dextromethorphan along with Prednisolone and Dexamethasone can be effective against novel Coronavirus disease (COVID-19).

The ongoing outbreak of Coronavirus disease 2019 (COVID-19) is a matter of great concern. Although the mortality rate caused by this virus is less than that of SARS and MERS, it is showing higher efficacy in terms of human-to-human transmission. Several strategies have been taken by scientists and researchers worldwide to combat this virus. Numerous phytochemicals and synthesized chemicals are under incessant inspection to obtain a potent anti-covid drug. Since, till now no precise therapy is available for covid patients, researchers are trying to categorize all possible anti-covid substances. Repurposing of drugs and combined drug therapy are becoming popular in treating such viral diseases. In this study, we are proposing the repurposing of three chemicals-Dextromethorphan, Prednisolone and Dexamethasone as anti-covid agents. We have used the tertiary structure of Coronavirus main protease (Mpro) with PDB ID 6LU7 as the target protein in this analysis. Molecular docking and dynamics study further revealed their synergistic effect against the COVID-19 protease protein.Communicated by Ramaswamy H. Sarma.

Natural compounds from Clerodendrum spp. as possible therapeutic candidates against SARS-CoV-2: An in silico investigation.

The COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 has rattled global public health, with researchers struggling to find specific therapeutic solutions. In this context, the present study employed an in silico approach to assess the inhibitory potential of the phytochemicals obtained from GC-MS analysis of twelve Clerodendrum species against the imperative spike protein, main protease enzyme Mpro and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2. An extensive molecular docking investigation of the phytocompounds at the active binding pockets of the viral proteins revealed promising inhibitory potential of the phytochemicals taraxerol, friedelin and stigmasterol. Decent physicochemical attributes of the compounds in accordance with Lipinski's rule of five and Veber's rule further established them as potential therapeutic candidates against SARS-CoV-2. Molecular mechanics-generalized Born surface area (MM-GBSA) binding free energy estimation revealed that taraxerol was the most promising candidate displaying the highest binding efficacy with all the concerned SARS-CoV-2 proteins included in the present analysis. Our observations were supported by robust molecular dynamics simulations of the complexes of the viral proteins with taraxerol for a timescale of 40 nanoseconds. It was striking to note that taraxerol exhibited better binding energy scores with the concerned viral proteins than the drugs that are specifically targeted against them. The present results promise to provide new avenues to further evaluate the potential of the phytocompound taraxerol in vitro and in vivo towards its successful deployment as a SARS-CoV-2 inhibitor and combat the catastrophic COVID-19.Communicated by Ramaswamy H. Sarma.