Korupensamine A, but not its atropisomer, korupensamine B, inhibits SARS-CoV-2 in vitro by targeting its main protease (Mpro)

By combining docking and molecular dynamics simulations, we explored a library of 65 mostly axially chiral naphthylisoquinoline alkaloids and their analogues, with most different molecular architectures and structural analogues, for their activity against SARS-CoV-2. Although natural biaryls are often regarded without consideration of their axial chirality, they can bind to protein targets in an atroposelective manner. By combining docking results with steered molecular dynamics simulations, we identified one alkaloid, korupensamine A, that atropisomer-specifically inhibited the main protease (Mpro) activity of SARS-CoV-2 significantly in comparison to the reference covalent inhibitor GC376 (IC50 = 2.52 ± 0.14 and 0.88 ± 0.15 μM, respectively) and reduced viral growth by five orders of magnitude in vitro (EC50 = 4.23 ± 1.31 μM). To investigate the binding pathway and mode of interaction of korupensamine A within the active site of the protease, we utilized Gaussian accelerated molecular dynamics simulations, which reproduced the docking pose of korupensamine A inside the active site of the enzyme. The study presents naphthylisoquinoline alkaloids as a new class of potential anti-COVID-19 agents. Graphical abstract Image 1

Korupensamine A, but not its atropisomer, korupensamine B, inhibits SARS-CoV-2 in vitro by targeting its main protease (Mpro).

By combining docking and molecular dynamics simulations, we explored a library of 65 mostly axially chiral naphthylisoquinoline alkaloids and their analogues, with most different molecular architectures and structural analogues, for their activity against SARS-CoV-2. Although natural biaryls are often regarded without consideration of their axial chirality, they can bind to protein targets in an atroposelective manner. By combining docking results with steered molecular dynamics simulations, we identified one alkaloid, korupensamine A, that atropisomer-specifically inhibited the main protease (Mpro) activity of SARS-CoV-2 significantly in comparison to the reference covalent inhibitor GC376 (IC50 = 2.52 ± 0.14 and 0.88 ± 0.15 µM, respectively) and reduced viral growth by five orders of magnitude in vitro (EC50 = 4.23 ± 1.31 µM). To investigate the binding pathway and mode of interaction of korupensamine A within the active site of the protease, we utilized Gaussian accelerated molecular dynamics simulations, which reproduced the docking pose of korupensamine A inside the active site of the enzyme. The study presents naphthylisoquinoline alkaloids as a new class of potential anti-COVID-19 agents.

Aloin A inhibits SARS CoV-2 replication by targeting its binding with ACE2 - Evidence from modeling-supported molecular dynamics simulation.

The current study aimed to expand on the recently published results and assess the inhibitory efficacy of aloin A against SARS CoV-2. In vitro testing of aloin A against SARS CoV-2 proteases (i.e., MPro and PLPro) showed weak to moderate activity (IC50 = 68.56 ± 1.13 µM and 24.77 ± 1.57 µM, respectively). However, aloin A was able to inhibit the replication of SARS CoV-2 in Vero E6 cells efficiently with an IC50 of 0.095 ± 0.022 µM. Depending on the reported poor permeability of aloin A alongside its insignificant protease inhibitory activities presented in this study, we ran a number of extensive virtual screenings and physics-based simulations to determine the compound's potential mode of action. As a result, RBD-ACE2 was identified as a key target for aloin A. Results from 600 ns-long molecular dynamics (MD) simulation experiments pointed to aloin A's role as an RBD-ACE2 destabilizer. Therefore, the results of this work may pave the way for further development of this scaffold and the eventual production of innovative anti-SARS CoV-2 medicines with several mechanisms of action.Communicated by Ramaswamy H. Sarma.

Mathematical model for the novel coronavirus (2019-nCOV) with clinical data using fractional operator.

Coronavirus infection (COVID-19) is a considerably dangerous disease with a high demise rate around the world. There is no known vaccination or medicine until our time because the unknown aspects of the virus are more significant than our theoretical and experimental knowledge. One of the most effective strategies for comprehending and controlling the spread of this epidemic is to model it using a powerful mathematical model. However, mathematical modeling with a fractional operator can provide explanations for the disease's possibility and severity. Accordingly, basic information will be provided to identify the kind of measure and intrusion that will be required to control the disease's progress. In this study, we propose using a fractional-order SEIARPQ model with the Caputo sense to model the coronavirus (COVID-19) pandemic, which has never been done before in the literature. The stability analysis, existence, uniqueness theorems, and numerical solutions of such a model are displayed. All results were numerically simulated using MATLAB programming. The current study supports the applicability and influence of fractional operators on real-world problems.

A Comprehensive In Silico Study of New Metabolites from Heteroxenia fuscescens with SARS-CoV-2 Inhibitory Activity.

Chemical investigation of the total extract of the Egyptian soft coral Heteroxenia fuscescens, led to the isolation of eight compounds, including two new metabolites, sesquiterpene fusceterpene A (1) and a sterol fuscesterol A (4), along with six known compounds. The structures of 1-8 were elucidated via intensive studies of their 1D, 2D-NMR, and HR-MS analyses, as well as a comparison of their spectral data with those mentioned in the literature. Subsequent comprehensive in-silico-based investigations against almost all viral proteins, including those of the new variants, e.g., Omicron, revealed the most probable target for these isolated compounds, which was found to be Mpro. Additionally, the dynamic modes of interaction of the putatively active compounds were highlighted, depending on 50-ns-long MDS. In conclusion, the structural information provided in the current investigation highlights the antiviral potential of H. fuscescens metabolites with 3ß,5α,6ß-trihydroxy steroids with different nuclei against SARS-CoV-2, including newly widespread variants.

Anti-otomycotic potential of nanoparticles of Moringa oleifera leaf extract: an integrated in vitro, in silico and phase 0 clinical study.

Otomycosis is a serious superficial mycotic infection of the outer ear canal caused by some pathogenic species of Candida and Aspergillus. The infection remains a challenge to clinicians owing to the incomplete efficacy of market-available antifungal agents and high recurrence rates. The Moringa oleifera leaf ethanol extract showed efficacy against Candida albicans SC5314, compared to Nystatin® as a reference with MIC values of 7 and 718.33 µg ml-1, respectively. The extract was mixed with lecithin and chitosan to give Moringa core/shell giant nanoparticles, with a good zeta potential (+59.2 mV), a suitable entrapment efficiency (61%) and an enhanced release reaching up to 90% at 8 h. Clinical isolates from oomycote patients were identified via DNA sequencing as Candida parapsilosis, Aspergillus niger and Aspergillus flavus, and the effect of the prepared nanoparticles was tested against them via disk diffusion assay to give inhibition zones of 75, 55 and 55 mm, compared to Nystatin® with 35, 25 and 20 mm, respectively. Interestingly, patients treated with the Moringa-loaded nanoparticles experienced improvement within 1 week with no recurrence for more than 3 months. To have some insight into the bioactive components in the Moringa extract, LC-HRMS-based identification has been employed which led to the annotation of 27 compounds. Subsequent comprehensive in silico investigation suggested some alkaloids to be responsible for the activity targeting the fungal 14-α-demethylase enzyme (CYP51B). Our study revealed that Moringa extract-loaded nanoparticles attained an enhanced antifungal efficacy compared to Nystatin® and therefore they can be employed against invasive and drug-resistant otomycotic infections.

MEMBRANOUS DEHISCENCE AFTER TRACHEAL RESECTION AND RECONSTRUCTION HEALED SPONTANEOUSLY WITH CONSERVATIVE TREATMENT

SESSION TITLE: Rare Cases in Cardiothoracic Surgery SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 12:25 pm - 01:25 pm INTRODUCTION: Membranous dehiscence after tracheal resection is an uncommon but deadly complication. It may present acutely with loss of airway, insidiously with progressive stridor, infection or subcutaneous emphysema, or asymptomatically. Treatment may be conservative if the separation is minimal but may require re-exploration if the defect is more severe. The extent of dehiscence amenable to conservative treatment is not well described in the literature. This case report describes the conservative treatment of a posterior membrane dehiscence. CASE PRESENTATION: A 50-year-old woman suffered from stridor due to tracheal stenosis after prolonged intubation from COVID-19. Endobronchial treatments were unsuccessful because of a malacic segment of airway. Via a cervical approach, approximately 2cm of malacic trachea was resected. Reconstruction was performed with a running suture of the posterior membrane and interrupted, figure-of-eight sutures of the anterior trachea. On postoperative day 5, the patient developed subcutaneous emphysema. A CT scan was obtained (Figure 1A), demonstrating disruption of the membranous portion of the anastomosis. As the patient's breathing was not affected, conservative treatment was preferred. She was encouraged to maintain her neck in a flexed position while continuously monitored with a pulse oximeter and treated with intravenous and aerosolized antibiotics. A repeat CT scan was obtained one week after (Figure 1B), showing no residual tracheal wall defect. Postoperative bronchoscopy showed that the posterior membrane had healed entirely. She remains asymptomatic on follow-up visits. DISCUSSION: Wound dehiscence after tracheal resection and reconstruction occurs in about 1-4% of the cases (1, 2), and it is associated with a significant morbidity and a 0.6% chance of mortality (1). We believe the membranous anastomosis failed because the posterior membrane was inflamed and adhered to the esophagus during the index operation. We did not want to perform a bronchoscopy in this situation, as positioning and coughing could exacerbate the dehiscence. As her breathing was unaffected at this point, we debated between a conservative or invasive approach. Conservative management is preferred for small defects and mild symptoms (3), but there is sparse further elaboration in the literature. Because the cartilaginous anastomosis appeared intact and she was breathing spontaneously, we decided to treat conservatively with expectant management. This included aggressive treatment with antibiotics to avoid infection and further anastomotic breakdown. More examples are needed to establish the likelihood of success with conservative treatment versus revisional surgery for partial dehiscence. CONCLUSIONS: Dehiscence after tracheal resection increases morbidity and mortality significantly. This is an example of a posterior membrane dehiscence that resolved spontaneously with conservative measures. Reference #1: Stock C, Gukasyan N, Muniappan A, Wright C, Mathisen D. Hyperbaric oxygen therapy for the treatment of anastomotic complications after tracheal resection and reconstruction. J Thorac Cardiovasc Surg. 2014;147(3):1030-5. Reference #2: Young A, Bigcas JLM. Tracheal Resection. [Updated 2022 Feb 16]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing;2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK563234/. Reference #3: Auchincloss HG, Wright CD. Complications after tracheal resection and reconstruction: prevention and treatment. J Thorac Dis. 2016;8(Suppl 2):S160-7. DISCLOSURES: No relevant relationships by Rocio Castillo-Larios No relevant relationships by Magdy El-Sayed Ahmed No relevant relationships by Sebastian Fernandez-Bussy No relevant relationships by daniel hernandez No relevant relationships by Samuel Jacob No relevant relationships by Ian Makey No relevant relationships by Sai Priyanka Pulipaka No relevant relationships b Mathew Thomas No relevant relationships by Alejandra Yu Lee-Mateus

New Halogenated Compounds from Halimeda macroloba Seaweed with Potential Inhibitory Activity against Malaria.

Malaria is one of the most important infectious diseases worldwide. The causative of the most severe forms of malaria, Plasmodium falciparum, has developed resistances against all the available antimalarial drugs. In the present study, the phytochemical investigation of the green seaweed Halimeda macroloba has afforded two new compounds 1-2, along with 4 known ones 3-6. The structures of the compounds had been confirmed using 1& 2D-NMR and HRESIMS analyses. Extensive machine-learning-supported virtual-screening suggested cytochrome-C enzyme as a potential target for compound 2. Docking, absolute-binding-free-energy (ΔGbinding) and molecular-dynamics-simulation (MDS) of compound 2 revealed the strong binding interaction of this compound with cytochrome-C. In vitro testing for crude extract and isolated compounds revealed the potential in vitro inhibitory activity of both extract and compound 2 against P. falciparum. The crude extract was able to inhibit the parasite growth with an IC50 value of 1.8 ± 0.35 µg/mL. Compound 2 also showed good inhibitory activity with an IC50 value of 3.2 ± 0.23 µg/mL. Meanwhile, compound 6 showed moderate inhibitory activity with an IC50 value of 19.3 ± 0.51 µg/mL. Accordingly, the scaffold of compound 2 can be considered as a good lead compound for the future development of new antimalarial agents.

Nature as a treasure trove of potential anti-SARS-CoV drug leads: a structural/mechanistic rationale† † Electronic supplementary information (ESI) available. See DOI: 10.1039/d0ra04199h

The novel Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is a potential factor for fatal illness and a tremendous concern for global public health. The COVID-19 pandemic has entered a dangerous new phase. In the context of drug discovery, the structurally-unique and chemically-diverse natural products have been valuable sources for drug leads. In this review, we report for potential candidates derived from natural sources with well-reported in vitro efficacy against SARS-CoV during the last decade. Additionally, a library of 496 phenolic metabolites was subjected to a computer-aided virtual screening against the active site of the recently reported SARS-CoV Main protease (Mpro). Analysis of physicochemical properties of these natural products has been carried out and presented for all the tested phenolic metabolites. Only three of the top candidates, viz. acetylglucopetunidin (31), isoxanthohumol (32) and ellagic acid (33), which are widely available in many edible fruits, obey both Lipinski's and Veber's rules of drug-likeness and thus possess high degrees of predicted bioavailability. These natural products are suggested as potential drug candidates for the development of anti-SARS-CoV-2 therapeutics in the near future. Potential drug candidates derived from natural sources are posed for the development of anti-SARS CoV-2 therapeutics.

In silico study of natural compounds from sesame against COVID-19 by targeting Mpro, PLpro and RdRp.

Natural products and traditional medicine products with known safety profiles are a promising source for the discovery of new drug leads. Natural products as sesame were reported to exhibit potential to protect from COVID-19 disease. In our study, the total methanolic extract of Sesamum indicum L. seeds (sesame) were led to isolation of seven known compounds, five lignan; sesamin 1, sesamolin 2, pinoresinol 3, hydroxymatairesinol 6, spicatolignan 7, together with two simple phenolic compounds; ferulic acid 4 and vanillic acid 5. All isolated compounds were evaluated in silico against three important SARS-CoV-2 protein targets; main protease (Mpro), papain-like protease (PLpro) and RNA-dependent RNA polymerase (RdRp) which possessed crucial role in replication and proliferation of the virus inside the human cell. The results revealed that compound 6 has the high affinity against the three main proteins, specially towards the SARS-CoV-2 Mpro that exceeded the currently used SARS-CoV-2 Mpro inhibitor darunavir as well as, exhibiting a similar binding energy at SARS CoV-2 PLpro when compared with the co-crystallized ligand. This activity continued to include the RdRp as it displayed a comparable docking score with remdesivir. Inferiorly, compounds 1 and 2 showed also similar triple inhibitory effect against the three main proteins while compound 7 exhibited a dual inhibitory effect against SARS CoV-2 PLPro and RdRp. Further molecular dynamic simulation experiments were performed to validate these docking experiments and to calculate their binding free energies (ΔGs). Compounds 1, 2, 3, 6, and 7 showed comparable binding stability inside the active site of each enzyme with ΔG values ranged from -4.9 to -8.8 kcal mol-1. All the compounds were investigated for their ADME and drug likeness properties, which showed acceptable ADME properties and obeying Lipinski's rule of five parameters. It can be concluded that the isolated compounds from sesame lignans could be an alternative source for the development of new natural leads against COVID-19.

In silico study of natural compounds from sesame against COVID-19 by targeting Mpro, PLpro and RdRp† † Electronic supplementary information (ESI) available. See DOI: 10.1039/d1ra03937g

Natural products and traditional medicine products with known safety profiles are a promising source for the discovery of new drug leads. Natural products as sesame were reported to exhibit potential to protect from COVID-19 disease. In our study, the total methanolic extract of Sesamum indicum L. seeds (sesame) were led to isolation of seven known compounds, five lignan;sesamin 1, sesamolin 2, pinoresinol 3, hydroxymatairesinol 6, spicatolignan 7, together with two simple phenolic compounds;ferulic acid 4 and vanillic acid 5. All isolated compounds were evaluated in silico against three important SARS-CoV-2 protein targets;main protease (Mpro), papain-like protease (PLpro) and RNA-dependent RNA polymerase (RdRp) which possessed crucial role in replication and proliferation of the virus inside the human cell. The results revealed that compound 6 has the high affinity against the three main proteins, specially towards the SARS-CoV-2 Mpro that exceeded the currently used SARS-CoV-2 Mpro inhibitor darunavir as well as, exhibiting a similar binding energy at SARS CoV-2 PLpro when compared with the co-crystallized ligand. This activity continued to include the RdRp as it displayed a comparable docking score with remdesivir. Inferiorly, compounds 1 and 2 showed also similar triple inhibitory effect against the three main proteins while compound 7 exhibited a dual inhibitory effect against SARS CoV-2 PLPro and RdRp. Further molecular dynamic simulation experiments were performed to validate these docking experiments and to calculate their binding free energies (ΔGs). Compounds 1, 2, 3, 6, and 7 showed comparable binding stability inside the active site of each enzyme with ΔG values ranged from −4.9 to −8.8 kcal mol−1. All the compounds were investigated for their ADME and drug likeness properties, which showed acceptable ADME properties and obeying Lipinski's rule of five parameters. It can be concluded that the isolated compounds from sesame lignans could be an alternative source for the development of new natural leads against COVID-19. Natural products and traditional medicine products with known safety profiles are a promising source for the discovery of new drug leads.

Neoechinulin A as a Promising SARS-CoV-2 Mpro Inhibitor: In Vitro and In Silico Study Showing the Ability of Simulations in Discerning Active from Inactive Enzyme Inhibitors.

The COVID-19 pandemic and its continuing emerging variants emphasize the need to discover appropriate treatment, where vaccines alone have failed to show complete protection against the new variants of the virus. Therefore, treatment of the infected cases is critical. This paper discusses the bio-guided isolation of three indole diketopiperazine alkaloids, neoechinulin A (1), echinulin (2), and eurocristatine (3), from the Red Sea-derived Aspergillus fumigatus MR2012. Neoechinulin A (1) exhibited a potent inhibitory effect against SARS-CoV-2 Mpro with IC50 value of 0.47 µM, which is comparable to the reference standard GC376. Despite the structural similarity between the three compounds, only 1 showed a promising effect. The mechanism of inhibition is discussed in light of a series of extensive molecular docking, classical and steered molecular dynamics simulation experiments. This paper sheds light on indole diketopiperazine alkaloids as a potential structural motif against SARS-CoV-2 Mpro. Additionally, it highlights the potential of different molecular docking and molecular dynamics simulation approaches in the discrimination between active and inactive structurally related Mpro inhibitors.

Aurasperone A Inhibits SARS CoV-2 In Vitro: An Integrated In Vitro and In Silico Study.

Several natural products recovered from a marine-derived Aspergillus niger were tested for their inhibitory activity against SARS CoV-2 in vitro. Aurasperone A (3) was found to inhibit SARS CoV-2 efficiently (IC50 = 12.25 µM) with comparable activity with the positive control remdesivir (IC50 = 10.11 µM). Aurasperone A exerted minimal cytotoxicity on Vero E6 cells (CC50 = 32.36 mM, SI = 2641.5) and it was found to be much safer than remdesivir (CC50 = 415.22 µM, SI = 41.07). To putatively highlight its molecular target, aurasperone A was subjected to molecular docking against several key-viral protein targets followed by a series of molecular dynamics-based in silico experiments that suggested Mpro to be its primary viral protein target. More potent anti-SARS CoV-2 Mpro inhibitors can be developed according to our findings presented in the present investigation.

SARS-CoV-2 Post Vaccinated Adverse Effects and Efficacy in the Egyptian Population.

Vaccines are the solution to overcome SARS-CoV-2. This study aimed to determine the post-Sinopharm vaccine safety-profile and immunity through antibody titers. Data were collected using a structured questionnaire from Egyptian participants who received two doses of Sinopharm vaccine. Data were divided into three parts, the first and second parts were to detect participants' post-first and second dose symptoms and practices, and the third for the results of IgG anti spike protein antibodies test and laboratory tests. Pain, redness, swelling at the injection site, headache, fatigue, and lethargy were the most common post-vaccine symptoms for both first and second doses. Most of the participants felt mild or no symptoms after vaccination. The symptoms started mostly during the first day post-vaccination and lasted for no more than two days. Forty-nine percent of the participants resulted in positive antibodies tests on day 18 post-vaccination. The average antibody level for vaccinated participants with past SARS-CoV-2 infection was much higher than that for non-past infected participants. These vaccines' administration methods need to be reevaluated by changing the dose, dose interval, adding a third dose, or mixing it with other vaccines with different techniques to improve their protection rates. Further studies are required to validate this finding.

Phytochemical and in silico studies for potential constituents from Centaurium spicatum as candidates against the SARS-CoV-2 main protease and RNA-dependent RNA polymerase.

In the present study, a new secoiridoid glycoside lisianthoside II 1, along with seven known compounds 2-8, were isolated from Centaurium spicatum L. In-silico molecular docking and molecular dynamic simulation against SARS-CoV-2 Main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) were conducted. The affinity docking scores revealed that 8 is the best bound ligand to Mpro active site with binding energy of -14.9877 kcal/mol (RSMD = 1.16 Å), while 6 was the highest against RdRp (-16.9572 kcal/mol, RMSD = 1.01 Å). Moreover, the molecular dynamic simulation revealed that 8 with a (ΔG) of -7.9 kcal/mol (RMSD value of 2.6 Å) and 6 (RMSD value of 1.6 Å) and binding free energy (ΔG) of -7.1 kcal/mol achieved the highest stability over 50 ns of MDS inside the Mpro and RdRp enzyme's active site, respectively. Hence, the isolated compounds could be a good lead for development of new leads targeting COVID-19.

Identifying the specific-targeted marine cerebrosides against SARS-CoV-2: an integrated computational approach.

Cerebrosides are a group of metabolites belonging to the glycosphingolipids class of natural products. So far, 167 cerebrosides, compounds 1-167, have been isolated from diverse marine organisms or microorganisms. The as yet smaller number of compounds that have been studied more in depth proves a potential against challenging diseases, such as cancer, a range of viral and bacterial diseases, as well as inflammation. This review provides a comprehensive summary on this so far under-explored class of compounds, their chemical structures, bioactivities, and their marine sources, with a full coverage to the end of 2020. Today, the global pandemic concern, COVID-19, has claimed millions of death cases around the world, making the development of anti-SARS-CoV-2 drugs urgently needed for such a battle. Accordingly, selected examples from all subclasses of cerebrosides were virtually screened for potential inhibition of SARS-CoV-2 proteins that are crucially involved in the viral-host interaction, viral replication, or in disease progression. The results highlight five cerebrosides that could preferentially bind to the hACE2 protein, with binding scores between -7.1 and -7.6 kcal mol-1 and with the docking poses determined underneath the first α1-helix of the protein. Moreover, the molecular interaction determined by molecular dynamic (MD) simulation revealed that renieroside C1 (60) is more conveniently involved in key hydrophobic interactions with the best stability, least deviation, least ΔG (-6.9 kcal mol-1) and an RMSD value of 3.6 Å. Thus, the structural insights assure better binding affinity and favorable molecular interaction of renieroside C1 (60) towards the hACE2 protein, which plays a crucial role in the biology and pathogenesis of SARS-CoV-2.

Chemical constituents from Limonium tubiflorum and their in silico evaluation as potential antiviral agents against SARS-CoV-2.

Wild plants growing in the Egyptian deserts are facing abiotic stress, which can lead to interesting & safe natural products possessing potential chemical profiles. Consequently, our study was designed to assess the phytochemical composition of the aerial parts of Limonium tubiflorum (family Plumbaginaceae) growing wild in Egypt for the first time. In addition, in silico screening and molecular dynamic simulation of all isolated phytoconstituents were run against the main protease (Mpro) and spike glycoprotein SARS-CoV-2 targets which displayed a crucial role in the replication of this virus. Our findings showed that the phytochemical investigation of 70% ethanol extract of L. tubiflorum aerial parts afforded six known flavonoids; myricetin 3-O-(2''-galloyl)-ß-d-galactopyranoside (1), myricetin 3-O-(2''-galloyl)-α-l-rhamnopyranoside (2), myricetin 3-O-(3''-galloyl)-α-l-rhamnopyranoside (3), myricetin 3-O-ß-d-galactopyranoside (5), apigenin (6), myricetin (7), along with two known phenolic acid derivatives; gallic acid (4) and ethyl gallate (8). Docking studies revealed that compounds (1) & (2) were the most effective compounds with binding energies of -17.9664 & -18.6652 kcal mol-1 against main protease and -18.9244 & -18.9272 kcal mol-1 towards spike glycoprotein receptors, respectively. The molecular dynamics simulation experiment agreed with the docking study and reported stability of compounds (1) and (2) against the selected targets which was proved by low RMSD for the tested components. Moreover, the structure-activity relationship revealed that the presence of the galloyl moiety is necessary for enhancement of the activity. Overall, the galloyl substructure of myricetin 3-O-glycoside derivatives (1 and 2) isolated from L. tubiflorum may be a possible lead for developing COVID-19 drugs. Further, in vitro and in vivo assays are recommended to support our in silico studies.

Efficacy of Ceftazidime and Cefepime in the Management of COVID-19 Patients: Single Center Report from Egypt.

The purpose of this study was to explore the value of using cefepime and ceftazidime in treating patients with COVID-19. A total of 370 (162 males) patients, with RT-PCR-confirmed cases of COVID-19, were included in the study. Out of them, 260 patients were treated with cefepime or ceftazidime, with the addition of steroids to the treatment. Patients were divided into three groups: Group 1: patients treated with cefepime (124 patients); Group 2: patients treated with ceftazidime (136 patients); Group 3 (control group): patients treated according to the WHO guidelines and the Egyptian COVID-19 management protocol (110 patients)/ Each group was classified into three age groups: 18-30, 31-60, and >60 years. The dose of either cefepime or ceftazidime was 1000 mg twice daily for five days. Eight milligrams of dexamethasone were used as the steroidal drug. Careful follow-ups for the patients were carried out. In vitro and in silico Mpro enzyme assays were performed to investigate the antiviral potential of both antibiotics. The mean recovery time for Group 1 was 12 days, for Group 2 was 13 days, and for Group 3 (control) was 19 days. No deaths were recorded, and all patients were recovered without any complications. For Group 1, the recovery time was 10, 12, and 16 days for the age groups 18-30, 30-60, and >60 years, respectively. For Group 2, the recovery time was 11, 13, and 15 days for the age groups 18-30, 30-60, and >60 years, respectively. For Group 3 (control), the recovery time was 15, 16, and 17 days for the age groups 18-30, 30-60, and >60 years, respectively. Both ceftazidime and cefepime showed very good inhibitory activity towards SARS CoV-2's Mpro, with IC50 values of 1.81 µM and 8.53 µM, respectively. In conclusion, ceftazidime and cefepime are efficient for the management of moderate and severe cases of COVID-19 due to their potential anti-SARS CoV-2 activity and low side effects, and, hence, the currently used complex multidrug treatment protocol can be replaced by the simpler one proposed in this study.

Bioguided Isolation of Cyclopenin Analogues as Potential SARS-CoV-2 Mpro Inhibitors from Penicillium citrinum TDPEF34.

SARS-CoV-2 virus mutations might increase its virulence, and thus the severity and duration of the ongoing pandemic. Global drug discovery campaigns have successfully developed several vaccines to reduce the number of infections by the virus. However, finding a small molecule pharmaceutical that is effective in inhibiting SARS-CoV-2 remains a challenge. Natural products are the origin of many currently used pharmaceuticals and, for this reason, a library of in-house fungal extracts were screened to assess their potential to inhibit the main viral protease Mpro in vitro. The extract of Penicillium citrinum, TDPEF34, showed potential inhibition and was further analysed to identify potential Mpro inhibitors. Following bio-guided isolation, a series of benzodiazepine alkaloids cyclopenins with good-to-moderate activity against SARS-CoV-2 Mpro were identified. The mode of enzyme inhibition of these compounds was predicted by docking and molecular dynamic simulation. Compounds 1 (isolated as two conformers of S- and R-isomers), 2, and 4 were found to have promising in vitro inhibitory activity towards Mpro, with an IC50 values range of 0.36-0.89 µM comparable to the positive control GC376. The in silico investigation revealed compounds to achieve stable binding with the enzyme active site through multiple H-bonding and hydrophobic interactions. Additionally, the isolated compounds showed very good drug-likeness and ADMET properties. Our findings could be utilized in further in vitro and in vivo investigations to produce anti-SARS-CoV-2 drug candidates. These findings also provide critical structural information that could be used in the future for designing potent Mpro inhibitors.

Marine Sulfated Polysaccharides as Promising Antiviral Agents: A Comprehensive Report and Modeling Study Focusing on SARS CoV-2.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) is a novel coronavirus strain that emerged at the end of 2019, causing millions of deaths so far. Despite enormous efforts being made through various drug discovery campaigns, there is still a desperate need for treatments with high efficacy and selectivity. Recently, marine sulfated polysaccharides (MSPs) have earned significant attention and are widely examined against many viral infections. This article attempted to produce a comprehensive report about MSPs from different marine sources alongside their antiviral effects against various viral species covering the last 25 years of research articles. Additionally, these reported MSPs were subjected to molecular docking and dynamic simulation experiments to ascertain potential interactions with both the receptor-binding domain (RBD) of SARS CoV-2's spike protein (S-protein) and human angiotensin-converting enzyme-2 (ACE2). The possible binding sites on both S-protein's RBD and ACE2 were determined based on how they bind to heparin, which has been reported to exhibit significant antiviral activity against SARS CoV-2 through binding to RBD, preventing the virus from affecting ACE2. Moreover, our modeling results illustrate that heparin can also bind to and block ACE2, acting as a competitor and protective agent against SARS CoV-2 infection. Nine of the investigated MSPs candidates exhibited promising results, taking into consideration the newly emerged SARS CoV-2 variants, of which five were not previously reported to exert antiviral activity against SARS CoV-2, including sulfated galactofucan (1), sulfated polymannuroguluronate (SPMG) (2), sulfated mannan (3), sulfated heterorhamnan (8), and chondroitin sulfate E (CS-E) (9). These results shed light on the importance of sulfated polysaccharides as potential SARS-CoV-2 inhibitors.