Arylcoumarin perturbs SARS-CoV-2 pathogenesis by targeting the S-protein/ACE2 interaction.

The vaccination drive against COVID-19 worldwide was quite successful. However, the second wave of infections was even more disastrous. There was a rapid increase in reinfections and human deaths due to the appearance of new SARS-CoV-2 variants. The viral genome mutations in the variants were acquired while passing through different human hosts that could escape antibodies in convalescent or vaccinated individuals. The treatment was based on oxygen supplements and supportive protocols due to the lack of a specific drug. In this study, we identified three lead inhibitors of arylated coumarin derivatives 4,6,8-tri(naphthalen-2-yl)-2H-chromen-2-one (NF1), 8-(4-hydroxyphenyl)-4,6-di(naphthalen-2-yl)-2H-chromen-2-one (NF12) and 8-(4-hydroxyphenyl)-3,6-di(naphthalen-2-yl)-2H-chromen-2-one (NF-13) that showed higher binding affinity towards the junction of SARS-CoV-2 spike glycoprotein (S-protein) and human angiotensin-converting enzyme 2 (ACE2) receptor. Using molecular docking analysis, we identified the putative binding sites of these potent inhibitors. Notably, molecular dynamics (MD) simulation and MM-PBSA studies confirmed that these inhibitors have the potential ability to bind Spike-protein/ACE2 protein complex with minimal energy. Further, the two major concerns are an adaptive mutation of spike proteins- N501Y and D614G which displayed strong affinity towards NF-13 in docking analysis. Additionally, in vitro and in vivo studies are required to confirm the above findings and develop the inhibitors as potential drugs against SARS-CoV-2.

Targeting virus-host interaction by novel pyrimidine derivative: an in silico approach towards discovery of potential drug against COVID-19.

The entire human population over the globe is currently facing appalling conditions due to the spread of infection from coronavirus disease-2019 (COVID-19). The spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) present on the surface of the virion mediates the virus entry into the host cells and therefore is targeted by several scientific groups as a novel drug target site. The spike glycoprotein binds to the human angiotensin-converting enzyme-2 (hACE2) cell surface receptor abundantly expressed in lung tissues, and this binding phenomenon is a primary determinant of cell tropism and pathogenesis. The binding and internalization of the virus is the primary and most crucial step in the process of infection, and therefore the molecules targeting the inhibition of this process certainly hold a significant therapeutic value. Thus, we systematically applied the computational techniques to identify the plausible inhibitor from a chosen set of well characterized diaryl pyrimidine analogues which may disrupt interfacial interaction of spike glycoprotein (S) at the surface of hACE2. Using molecular docking, molecular dynamics (MD) simulation and binding free energy calculation, we have identified AP-NP (2-(2-amino-5-(naphthalen-2-yl)pyrimidin-4-yl)phenol), AP-3-OMe-Ph (2-(2-amino-5-(3-methoxyphenyl)pyrimidin-4-yl)phenol) and AP-4-Me-Ph (2-(2-amino-5-(p-tolyl) pyrimidin-4-yl)phenol) from a group of diaryl pyrimidine derivatives which appears to bind at the interface of the hACE2-S complex with low binding free energy. Thus, pyrimidine derivative AP-NP may be explored as an effective inhibitor for hACE2-S complex. Furthermore, in vitro and in vivo studies will strengthen the use of these inhibitors as suitable drug candidates against SARS-COV-2. Communicated by Ramaswamy H. Sarma.

Combining SARS-CoV-2 Proofreading Exonuclease and RNA-Dependent RNA Polymerase Inhibitors as a Strategy to Combat COVID-19: A High-Throughput in silico Screening.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people worldwide. Currently, many clinical trials in search of effective COVID-19 drugs are underway. Viral RNA-dependent RNA polymerase (RdRp) remains the target of choice for prophylactic or curative treatment of COVID-19. Nucleoside analogs are the most promising RdRp inhibitors and have shown effectiveness in vitro, as well as in clinical settings. One limitation of such RdRp inhibitors is the removal of incorporated nucleoside analogs by SARS-CoV-2 exonuclease (ExoN). Thus, ExoN proofreading activity accomplishes resistance to many of the RdRp inhibitors. We hypothesize that in the absence of highly efficient antivirals to treat COVID-19, combinatorial drug therapy with RdRp and ExoN inhibitors will be a promising strategy to combat the disease. To repurpose drugs for COVID-19 treatment, 10,397 conformers of 2,240 approved drugs were screened against the ExoN domain of nsp14 using AutoDock VINA. The molecular docking approach and detailed study of interactions helped us to identify dexamethasone metasulfobenzoate, conivaptan, hesperidin, and glycyrrhizic acid as potential inhibitors of ExoN activity. The results were further confirmed using molecular dynamics (MD) simulations and molecular mechanics combined with generalized Born model and solvent accessibility method (MM-GBSA) calculations. Furthermore, the binding free energy of conivaptan and hesperidin, estimated using MM-GBSA, was -85.86 ± 0.68 and 119.07 ± 0.69 kcal/mol, respectively. Based on docking, MD simulations and known antiviral activities, and conivaptan and hesperidin were identified as potential SARS-CoV-2 ExoN inhibitors. We recommend further investigation of this combinational therapy using RdRp inhibitors with a repurposed ExoN inhibitor as a potential COVID-19 treatment.

Essential functional molecules associated with SARS-CoV-2 infection: Potential therapeutic targets for COVID-19.

The whole world is still suffering substantially from the coronavirus disease 2019 (COVID-19) outbreak. Several protein-based molecules that are associated with the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which are essential for its functionality, survival, and pathogenesis have been identified and are considered as potential therapeutic targets. These protein-based molecules are either structural/non-structural components of SARS-CoV-2 or host factors, which play a crucial role in this infection. Developing drug molecules against these essential functional molecules to hinder their regular functioning and associated physiological pathways could be promising for successful clinical management of this novel coronavirus infection. The review aims to highlight the functional molecules that play crucial roles in SARS-CoV-2 pathogenesis. We have emphasized how these potential druggable targets could be beneficial in tackling the COVID-19 crisis.

Nucleic acid-based therapy for coronavirus disease 2019.

The coronavirus disease 2019 (COVID-19), the pandemic that originated in China has already spread into more than 190 countries, resulting in huge loss of human life and many more are at the stake of losing it; if not intervened with the best therapeutics to contain the disease. For that aspect, various scientific groups are continuously involved in the development of an effective line of treatment to control the novel coronavirus from spreading rapidly. Worldwide scientists are evaluating various biomolecules and synthetic inhibitors against COVID-19; where the nucleic acid-based molecules may be considered as potential drug candidates. These molecules have been proved potentially effective against SARS-CoV, which shares high sequence similarity with SARS-CoV-2. Recent advancements in nucleic acid-based therapeutics are helpful in targeted drug delivery, safely and effectively. The use of nucleic acid-based molecules also known to regulate the level of gene expression inside the target cells. This review mainly focuses on various nucleic acid-based biologically active molecules and their therapeutic potentials in developing vaccines for SARS-CoV-2.

Convalescent plasma therapy: a promising coronavirus disease 2019 treatment strategy.

The world is passing through a very difficult phase due to the coronavirus disease 2019 (COVID-19) pandemic, which has disrupted almost all spheres of life. Globally, according to the latest World Health Organization report (10 August 2020), COVID-19 has affected nearly 20 million lives, causing 728 013 deaths. Due to the lack of specific therapeutic drugs and vaccines, the outbreak of disease has spawned a corpus of contagious infection all over the world, day by day, without control. As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a very rapid infection rate, it is essential to develop a novel ameliorative and curative strategy as quickly as possible. Convalescent plasma (CP) therapy is a type of adaptive immunity that has already been found to be effective in confronting several infectious diseases from the last two decades. For example, CP therapy was used in the treatment of viral-induced diseases like SARS-CoV epidemics, Middle East respiratory syndrome coronavirus (MERS-CoV) pandemics, Ebola epidemics and H1N1 pandemic. In this review, we have mainly focused on the therapeutic role of CP therapy and its neutralizing effect to fight against the COVID-19 outbreak.

BCG vaccination strategy implemented to reduce the impact of COVID-19: Hype or Hope?

The Bacillus Calmette-Guerin vaccine (BCG vaccine) designed to prevent tuberculosis in children has been shown to induce a adaptive immune response in the body to fight against bacteria as well as other parasites and viruses. This knowledge has been reciprocated to generate the idea that this vaccine can also offer protection against severe acute respiratory syndrome coronavirus-2 (SARS-COV-2). Some recent pre-print articles have highlighted that countries with mass BCG immunizations seems to have a lower incidence of coronavirus disease 2019 (COVID-19) compared to those without BCG immunization. There are yet no experimental proof of any such association and the world health organisation (WHO) is currently testing the theory with clinical trials on selected cohorts. Epidemiologists and other scientific experts has expressed both their hope and concern simultaneously regarding the success theory of BCG vaccination to prevent COVID-19. Though its still not verified in any way whether the BCG vaccination can actually prevent COVID-19 or not but we believe a thorough analytical research in this regard is indeed worth a shot.

Targeting SARS-CoV-2 spike protein of COVID-19 with naturally occurring phytochemicals: an in silico study for drug development.

Spike glycoprotein, a class I fusion protein harboring the surface of SARS-CoV-2 (SARS-CoV-2S), plays a seminal role in the viral infection starting from recognition of the host cell surface receptor, attachment to the fusion of the viral envelope with the host cells. Spike glycoprotein engages host Angiotensin-converting enzyme 2 (ACE2) receptors for entry into host cells, where the receptor recognition and attachment of spike glycoprotein to the ACE2 receptors is a prerequisite step and key determinant of the host cell and tissue tropism. Binding of spike glycoprotein to the ACE2 receptor triggers a cascade of structural transitions, including transition from a metastable pre-fusion to a post-fusion form, thereby allowing membrane fusion and internalization of the virus. From ancient times people have relied on naturally occurring substances like phytochemicals to fight against diseases and infection. Among these phytochemicals, flavonoids and non-flavonoids have been the active sources of different anti-microbial agents. We performed molecular docking studies using 10 potential naturally occurring compounds (flavonoids/non-flavonoids) against the SARS-CoV-2 spike protein and compared their affinity with an FDA approved repurposed drug hydroxychloroquine (HCQ). Further, our molecular dynamics (MD) simulation and energy landscape studies with fisetin, quercetin, and kamferol revealed that these molecules bind with the hACE2-S complex with low binding free energy. The study provided an indication that these molecules might have the potential to perturb the binding of hACE2-S complex. In addition, ADME analysis also suggested that these molecules consist of drug-likeness property, which may be further explored as anti-SARS-CoV-2 agents. Communicated by Ramaswamy H. Sarma.