Analysis of Conocurvone, Ganoderic acid A and Oleuropein molecules against the main protease molecule of COVID-19 by in silico approaches: Molecular dynamics docking studies.

Traditional medicines against COVID-19 have taken important outbreaks evidenced by multiple cases, controlled clinical research, and randomized clinical trials. Furthermore, the design and chemical synthesis of protease inhibitors, one of the latest therapeutic approaches for virus infection, is to search for enzyme inhibitors in herbal compounds to achieve a minimal amount of side-effect medications. Hence, the present study aimed to screen some naturally derived biomolecules with anti-microbial properties (anti-HIV, antimalarial, and anti-SARS) against COVID-19 by targeting coronavirus main protease via molecular docking and simulations. Docking was performed using SwissDock and Autodock4, while molecular dynamics simulations were performed by the GROMACS-2019 version. The results showed that Oleuropein, Ganoderic acid A, and conocurvone exhibit inhibitory actions against the new COVID-19 proteases. These molecules may disrupt the infection process since they were demonstrated to bind at the coronavirus major protease's active site, affording them potential leads for further research against COVID-19.

Known *Anti Sars-Cov Protease Inhibitors* On Sars-Cov-2 Related Intracellular Reception Sites: *Docking Interaction* And Computer Aided Optimization Of Molecular Structure For *Chemioselective Interactions*

Molecular docking and molecular dynamics aided virtual search of OliveNet™ directory identified potential secoiridoids that combat SARS-CoV-2 entry, replication, and associated hyperinflammatory responses. OliveNet™ is an active directory of phytochemicals obtained from different parts of the olive tree, Olea europaea (Oleaceae). Olive oil, olive fruits containing phenolics, known for their health benefits, are indispensable in the Mediterranean and Arabian diets. Secoiridoids is the largest group of olive phenols and is exclusive to the olive fruits. Functional food like olive fruits could help prevent and alleviate viral disease at an affordable cost. A systematized virtual search of 932 conformers of 78 secoiridoids utilizing Autodock Vina, followed by precision docking using Idock and Smina indicated that Nüzhenide oleoside (NZO), Oleuropein dimer (OED), and Dihydro oleuropein (DHO) blocked the SARSCoV-2 spike (S) protein-ACE-2 interface;Demethyloleuropein (DMO), Neo-nüzhenide (NNZ), and Nüzhenide (NZE) blocked the SARS-CoV-2 main protease (Mpro). Molecular dynamics (MD) simulation of the NZO-S-protein-ACE-2 complex by Desmond revealed stability during 50 ns. RMSD of the NZO-S-protein-ACE-2 complex converged at 2.1 Å after 20 ns. During MD, the interaction fractions confirmed multiple interactions of NZO with Lys417, a crucial residue for inhibition of S protein. MD of DMO-Mpro complex proved its stability as the RMSD converged at 1.6 Å. Analysis of interactions during MD confirmed the interaction of Cys145 of Mpro with DMO and, thus, its inhibition. The docking predicted IC50 of NZO and DMO was 11.58 and 6.44 μM, respectively. Molecular docking and dynamics of inhibition of the S protein and Mpro by NZO and DMO correlated well. Docking of the six-hit secoiridoids to IL1R, IL6R, and TNFR1, the receptors of inflammatory cytokines IL1β, IL6, and TNFα, revealed the anti-inflammatory potential except for DHO. Due to intricate structures, the secoiridoids violated Lipinski's rule of five. However, the drug scores of secoiridoids supported their use as drugs. The ADMET predictions implied that the secoiridoids are non-toxic and pose low oral absorption. Secoiridoids need further optimization and are a suitable lead for the discovery of anti-SARS-CoV-2 therapeutics. For the moment, olive secoiridoids presents an accessible mode of prevention and therapy of SARS-CoV-2 infection.

Efficacy of olive leaves extract on the outcomes of hospitalized covid-19 patients: A randomized, triple-blinded clinical trial.

INTRODUCTION: Since the emergence of the novel coronavirus, herbal medicine has been considered a treatment for COVID-19 patients. This study was done to determine the efficacy of olive leaf extract on the outcomes of COVID-19 patients. MATERIALS AND METHODS: This randomized, triple-blinded clinical trial was conducted on hospitalized COVID-19 patients. Using block randomization, eligible patients were allocated to the following groups: intervention A received olive leaf extract (250 mg every 12 hours for five days), intervention B received olive leaf extract (500 mg every 12 hours for five days), and the control group received placebo (every 12 hours for five days). The outcomes (vital signs, laboratory tests, and length of hospitalization) were compared by group. RESULTS: Of the 150 patients randomized into groups, 141 completed the follow-up and were analyzed. On the fifth day of hospitalization, body temperature (MD=0.34, P<0.001), pulse rate (MD=5.42, P=0.016), respiratory rate (MD=1.66, P=0.001), ESR (MD=13.55, P<0.001), and CRP (MD=15.68, P<0.001) of intervention A were significantly lower than the control group, while oxygen saturation (MD= -1.81, P=0.001) of intervention A was significantly higher than the control group. Furthermore, body temperature (MD=0.30, P=0.001), pulse rate (MD=5.29, P=0.022), respiratory rate (MD=1.41, P=0.006), ESR (MD=14.79, P<0.001), and CRP (MD=16.28, P<0.001) of intervention B were significantly lower than the control group, while oxygen saturation (MD= -2.38, P<0.001) of intervention B was significantly higher than the control group. CONCLUSION: Olive leaf extract can improve the clinical status of the patients and decrease the length of hospitalization.

High-temperature Thin-layer Drying Kinetic of Cultivated and Wild Algerian Olive Leaves

Olive leaves (OLs) are well known for being rich in oleuropein, their main bioactive molecule which has recently been attracting great interest from the scientific community due to its antiviral properties, including Covid-19 disease. Furthermore, the high-temperature/ short-time drying process has found applications for various plants and food processing, which might be also implemented for the drying of OLs. This study focuses on: 1. the mathematical modeling of thin-layer high-temperature-drying (HTD) kinetic of olive (var. Chemlal and Oleaster) leaves, and 2. the determination of HTD effect on some physicochemical properties (oleuropein, chlorophylls, and CIELab color parameters) of the dried olive leaves (DOLs). For this, four drying temperatures (100, 120, 140, and 160 degrees C) were applied. For comparison purposes, low-temperature DOL samples were also prepared. The obtained data have shown that among the tens tested mathematical models, the Midilli et al. model describes more correctly experimental data for all drying temperatures and for both olive leaf varieties (R-2 = 0.9960, SEE = 0.0085, RMSE = 0.0165 and chi(2) = 0.0006). Moreover, the results show that the HTD at 120 and 160 degrees C does not differ from freeze-drying in terms of oleuropein retention (p < 0.05), highlighting the technological interest in the high-temperature/short-time drying process. Considering the biological value of oleuropein, in particular its antiviral activity, the study deserves further investigation in order to elucidate certain questions such as the storability of DOLs, and their valorization as fortification ingredient in food and pharmaceutical formulations, evaluation in vitro of their biological activities, etc.

PHYSICOCHEMICAL INVESTIGATION OF ANTI-COVID19 DRUGS USING SEVERAL MEDICINAL PLANTS

The goal of this paper was determining the physical and chemical properties of some medicinal plants which are used against the Covid19 symptoms. In this work, seven medicinal species for the most frequently symptoms of Covid19 disease such as fever, cough, sore throat, shortness of breath, anorexia, muscle-joint pain, headache and Nausea-vomiting based on the fidelity level index has been accomplished. Positive stranded RNA viruses, coronaviruses (CoVs), can infect humans and multiple species of animals through enteric, respiratory, and central nervous system diseases with attractive targets for designing anti- Covid19 conjunction. In this work, it has been investigated the compounds of kaempferol, quercetin, demethoxycurcumine, naringenin, apigenine-7-glucoside, oleuropein and catechin as a probable anti pandemic Covid19 receptor derived from medicinal plants. Anti-Covid19 through the hydrogen bonding using the physicochemical properties including heat of formation, Gibbs free energy, electronic energy, charge distribution of active parts in the hydrogen bonding, NMR estimation of medicinal ingredients jointed to the database amino acids fragment of Tyr-Met-His as the selective zone of the Covid19, positive frequency and intensity of different normal modes of these structures have been evaluated. The theoretical calculations were done at various levels of theory to gain the more accurate equilibrium geometrical results, and IR spectral data for each of the complex proposed drugs of N-terminal or O-terminal auto-cleavage substrate were individually determined to elucidate the structural flexibility and substrate binding of seven medicinal plants jointed to active site of Covid19 molecule. A comparison of these structures with two configurations provides new insights for the design of substrate-based anti-targeting Covid19. This indicates a feasible model for designing wide-spectrum of anti- Covid19 drugs. The structure-based optimization of these structures has yielded two more efficacious lead compounds, N and O atoms through forming the hydrogen bonding (H-bonding) with potent anti- Covid19. Finally, two medicinal ingredients of apigenine-7-glucoside and demethoxycurcumine jointed to TMH have directed to a Monte Carlo (MC) simulation. The results strongly suggest that the different data observed in the apigenine-7-glucoside and demethoxycurcumine in the solvent is principally due to basis set functions, induced by a change in polarity of the environment. It is clear that an increase in the dielectric constants enhances the stability of these anti-Covid19 drugs.

Oleuropein as a Potent Compound against Neurological Complications Linked with COVID-19: A Computational Biology Approach.

The association of COVID-19 with neurological complications is a well-known fact, and researchers are endeavoring to investigate the mechanistic perspectives behind it. SARS-CoV-2 can bind to Toll-like receptor 4 (TLR-4) that would eventually lead to α-synuclein aggregation in neurons and stimulation of neurodegeneration pathways. Olive leaves have been reported as a promising phytotherapy or co-therapy against COVID-19, and oleuropein is one of the major active components of olive leaves. In the current study, oleuropein was investigated against SARS-CoV-2 target (main protease 3CLpro), TLR-4 and Prolyl Oligopeptidases (POP), to explore oleuropein potency against the neurological complications associated with COVID-19. Docking experiments, docking validation, interaction analysis, and molecular dynamic simulation analysis were performed to provide insight into the binding pattern of oleuropein with the three target proteins. Interaction analysis revealed strong bonding between oleuropein and the active site amino acid residues of the target proteins. Results were further compared with positive control lopinavir (3CLpro), resatorvid (TLR-4), and berberine (POP). Moreover, molecular dynamic simulation was performed using YASARA structure tool, and AMBER14 force field was applied to examine an 100 ns trajectory run. For each target protein-oleuropein complex, RMSD, RoG, and total potential energy were estimated, and 400 snapshots were obtained after each 250 ps. Docking analyses showed binding energy as -7.8, -8.3, and -8.5 kcal/mol for oleuropein-3CLpro, oleuropein-TLR4, and oleuropein-POP interactions, respectively. Importantly, target protein-oleuropein complexes were stable during the 100 ns simulation run. However, an experimental in vitro study of the binding of oleuropein to the purified targets would be necessary to confirm the present study outcomes.

In silico investigation to identify potential small molecule inhibitors of the RNA-dependent RNA polymerase (RdRp) nidovirus RdRp-associated nucleotidyltransferase domain.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) is a promising target for antiviral drugs. In this study, a chemical library (n = 300) was screened against the nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain. Blind docking was performed using a selection of 30 compounds and nine ligands were chosen based on their docking scores, safety profile, and availability. Using cluster analysis on a 10 microsecond molecular dynamics simulation trajectory (from D.E. Shaw Research), the compounds were docked to the different conformations. On the basis of our modelling studies, oleuropein was identified as a potential lead compound.

Olive Oil Consumption can Prevent Non-communicable Diseases and COVID-19: A Review.

The Mediterranean diet is appraised as the premier dietary regimen, and its espousal is correlated with the prevention of degenerative diseases and extended longevity. The consumption of olive oil stands out as the most peculiar feature of the Mediterranean diet. Olive oil rich in various bioactive compounds like oleanolic acid, oleuropein, oleocanthal, and hydroxytyrosol is known for its antiinflammatory as well as cardioprotective property. Recently in silico studies have indicated that phytochemicals present in olive oil are a potential candidate to act against SARS-CoV-2. Although there are many extensive studies on olive oil and its phytochemical composition, however, some lacunas persist in understanding how the phytochemical composition of olive oil is dependent on upstream processing. The signaling pathways regulated by olive oil in the restriction of various diseases are also not clear. For answering these queries, a detailed search of research and review articles published between 1990 to 2019 were reviewed. Olive oil consumption was found to be advantageous for various chronic non-communicable diseases. Olive oil's constituents are having potent anti-inflammatory activities and thus restrict the progression of various inflammation-linked diseases ranging from arthritis to cancer. But it is also notable that the amount and nature of the phytochemical composition of household olive oil are regulated by its upstream processing, and the physicochemical properties of this oil can give a hint regarding the manufacturing method as well as its therapeutic effect. Moreover, daily uptake of olive oil should be monitored as excessive intake can cause body weight gain and a change in the basal metabolic index. So, it can be concluded that the olive oil consumption is beneficial for human health, and particularly for the prevention of cardiovascular diseases, breast cancer, and inflammation. The simple way of processing olive oil is to maintain the polyphenol constituents, whichprovide the protection against noncommunicable diseases and SARS-CoV-2.