In Silico Screening of Drugs That Target Different Forms of E Protein for Potential Treatment of COVID-19

Recently the E protein of SARS-CoV-2 has become a very important target in the potential treatment of COVID-19 since it is known to regulate different stages of the viral cycle. There is biochemical evidence that E protein exists in two forms, as monomer and homopentamer. An in silico screening analysis was carried out employing 5852 ligands (from Zinc databases), and performing an ADMET analysis, remaining a set of 2155 compounds. Furthermore, docking analysis was performed on specific sites and different forms of the E protein. From this study we could identify that the following ligands showed the highest binding affinity: nilotinib, dutasteride, irinotecan, saquinavir and alectinib. We carried out some molecular dynamics simulations and free energy MM–PBSA calculations of the protein–ligand complexes (with the mentioned ligands). Of worthy interest is that saquinavir, nilotinib and alectinib are also considered as a promising multitarget ligand because it seems to inhibit three targets, which play an important role in the viral cycle. On the other side, saquinavir was shown to be able to bind to E protein both in its monomeric as well as pentameric forms. Finally, further experimental assays are needed to probe our hypothesis derived from in silico studies.

In Silico Screening of Drugs That Target Different Forms of E Protein for Potential Treatment of COVID-19.

Recently the E protein of SARS-CoV-2 has become a very important target in the potential treatment of COVID-19 since it is known to regulate different stages of the viral cycle. There is biochemical evidence that E protein exists in two forms, as monomer and homopentamer. An in silico screening analysis was carried out employing 5852 ligands (from Zinc databases), and performing an ADMET analysis, remaining a set of 2155 compounds. Furthermore, docking analysis was performed on specific sites and different forms of the E protein. From this study we could identify that the following ligands showed the highest binding affinity: nilotinib, dutasteride, irinotecan, saquinavir and alectinib. We carried out some molecular dynamics simulations and free energy MM-PBSA calculations of the protein-ligand complexes (with the mentioned ligands). Of worthy interest is that saquinavir, nilotinib and alectinib are also considered as a promising multitarget ligand because it seems to inhibit three targets, which play an important role in the viral cycle. On the other side, saquinavir was shown to be able to bind to E protein both in its monomeric as well as pentameric forms. Finally, further experimental assays are needed to probe our hypothesis derived from in silico studies.

Parameters to Predict the Outcome of Severe and Critical COVID-19 Patients when Admitted to the Hospital.

Manifestations of COVID-19 are diverse and range from asymptomatic to severe, critical illness and death. Cases requiring hospital care (in severe and critical illnesses) are associated with comorbidities and hyperactivation of the immune system. Therefore, in this exploratory observational study, we analyzed which parameters are associated with mortality. We evaluated: demographic characteristics (age, sex and comorbidities), laboratory data (albumin, leukocytes, lymphocytes, platelets, ferritin), days of hospital stay, interleukins (IL-2, IL-6, IL-7, IL-10, IL-17) and sP-selectin in 40 Mexican patients admitted to medical emergencies with a confirmed diagnosis of COVID-19, a complete clinical record, and who signed the informed consent. Twenty severe (they required intermediate care with non-invasive ventilation) and twenty critically ill patients (they required mechanical ventilation) were classified, and these were subsequently compared with healthy and recovered subjects. A significant difference was found between the hospitalized groups in the parameters of age, ferritin, days of hospital stay and death with p values = 0.0145, p = 0.0441, p = 0.0001 and p = 0.0001, respectively. In the determination of cytokines and P-selectin, a significant difference was found between the following groups: recovered patients and healthy volunteers compared with hospitalized patients in severe and critical condition. Importantly, IL-7 remained elevated one year later in recovered patients. Taken together, these values determined at the time of hospital admission could be useful to monitor patients closely and evaluate in-hospital progress, hospital discharge, and out-of-hospital progress.

The Advantage of Using Immunoinformatic Tools on Vaccine Design and Development for Coronavirus.

After the outbreak of SARS-CoV-2 by the end of 2019, the vaccine development strategies became a worldwide priority. Furthermore, the appearances of novel SARS-CoV-2 variants challenge researchers to develop new pharmacological or preventive strategies. However, vaccines still represent an efficient way to control the SARS-CoV-2 pandemic worldwide. This review describes the importance of bioinformatic and immunoinformatic tools (in silico) for guide vaccine design. In silico strategies permit the identification of epitopes (immunogenic peptides) which could be used as potential vaccines, as well as nonacarriers such as: vector viral based vaccines, RNA-based vaccines and dendrimers through immunoinformatics. Currently, nucleic acid and protein sequential as well structural analyses through bioinformatic tools allow us to get immunogenic epitopes which can induce immune response alone or in complex with nanocarriers. One of the advantages of in silico techniques is that they facilitate the identification of epitopes, while accelerating the process and helping to economize some stages of the development of safe vaccines.

In Silico Drug Repositioning to Target the SARS-CoV-2 Main Protease as Covalent Inhibitors Employing a Combined Structure-Based Virtual Screening Strategy of Pharmacophore Models and Covalent Docking.

The epidemic caused by the SARS-CoV-2 coronavirus, which has spread rapidly throughout the world, requires urgent and effective treatments considering that the appearance of viral variants limits the efficacy of vaccines. The main protease of SARS-CoV-2 (Mpro) is a highly conserved cysteine proteinase, fundamental for the replication of the coronavirus and with a specific cleavage mechanism that positions it as an attractive therapeutic target for the proposal of irreversible inhibitors. A structure-based strategy combining 3D pharmacophoric modeling, virtual screening, and covalent docking was employed to identify the interactions required for molecular recognition, as well as the spatial orientation of the electrophilic warhead, of various drugs, to achieve a covalent interaction with Cys145 of Mpro. The virtual screening on the structure-based pharmacophoric map of the SARS-CoV-2 Mpro in complex with an inhibitor N3 (reference compound) provided high efficiency by identifying 53 drugs (FDA and DrugBank databases) with probabilities of covalent binding, including N3 (Michael acceptor) and others with a variety of electrophilic warheads. Adding the energy contributions of affinity for non-covalent and covalent docking, 16 promising drugs were obtained. Our findings suggest that the FDA-approved drugs Vaborbactam, Cimetidine, Ixazomib, Scopolamine, and Bicalutamide, as well as the other investigational peptide-like drugs (DB04234, DB03456, DB07224, DB7252, and CMX-2043) are potential covalent inhibitors of SARS-CoV-2 Mpro.

Liver disorders in COVID-19, nutritional approaches and the use of phytochemicals.

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has affected millions of people globally. It was declared a pandemic by the World Health Organization in March 2020. The hyperinflammatory response to the entry of SARS-CoV-2 into the host through angiotensin-converting enzyme 2 is the result of a "cytokine storm" and the high oxidative stress responsible for the associated symptomatology. Not only respiratory symptoms are reported, but gastrointestinal symptoms (diarrhea, vomiting, and nausea) and liver abnormalities (high levels of aspartate aminotransferase, alanine aminotransferase transaminases, and bilirubin) are observed in at least 30% of patients. Reduced food intake and a delay in medical services may lead to malnutrition, which increases mortality and poor outcomes. This review provides some strategies to identify malnutrition and establishes nutritional approaches for the management of COVID-19 and liver injury, taking energy and nutrient requirements and their impact on the immune response into account. The roles of certain phytochemicals in the prevention of the disease or as promising target drugs in the treatment of this disease are also considered.

Repositioning of Ligands That Target the Spike Glycoprotein as Potential Drugs for SARS-CoV-2 in an In Silico Study.

The worldwide health emergency of the SARS-CoV-2 pandemic and the absence of a specific treatment for this new coronavirus have led to the use of computational strategies (drug repositioning) to search for treatments. The aim of this work is to identify FDA (Food and Drug Administration)-approved drugs with the potential for binding to the spike structural glycoprotein at the hinge site, receptor binding motif (RBM), and fusion peptide (FP) using molecular docking simulations. Drugs that bind to amino acids are crucial for conformational changes, receptor recognition, and fusion of the viral membrane with the cell membrane. The results revealed some drugs that bind to hinge site amino acids (varenicline, or steroids such as betamethasone while other drugs bind to crucial amino acids in the RBM (naldemedine, atovaquone, cefotetan) or FP (azilsartan, maraviroc, and difluprednate); saquinavir binds both the RBM and the FP. Therefore, these drugs could inhibit spike glycoprotein and prevent viral entry as possible anti-COVID-19 drugs. Several drugs are in clinical studies; by focusing on other pharmacological agents (candesartan, atovaquone, losartan, maviroc and ritonavir) in this work we propose an additional target: the spike glycoprotein. These results can impact the proposed use of treatments that inhibit the first steps of the virus replication cycle.