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.

Application of Ultraviolet-C Radiation and Gaseous Ozone for Microbial Inactivation on Different Materials.

With the advent of the COVID-19 pandemic, there has been a global incentive for applying environmentally sustainable and rapid sterilization methods, such as ultraviolet-C radiation (UVC) and ozonation. Material sterilization is a requirement for a variety of industries, including food, water treatment, clothing, healthcare, medical equipment, and pharmaceuticals. It becomes inevitable when devices and items like protective equipment are to be reused on/by different persons. This study presents novel findings on the performance of these sterilization methods using four microorganisms (Escherichia coli , Staphylococcus aureus , Candida albicans , and Aspergillus fumigatus) and six material substrates (stainless steel, polymethyl methacrylate, copper, surgical facemask, denim, and a cotton-polyester fabric). The combination of both ozone and UVC generally yields improved performance compared to their respective applications for the range of materials and microorganisms considered. Furthermore, the effectiveness of both UVC and ozone was higher when the fungi utilized were smeared onto the nonabsorbent materials than when 10 µL droplets were placed on the material surfaces. This dependence on the contaminating liquid surface area was not exhibited by the bacteria. This study highlights the necessity of adequate UVC and ozone dosage control as well as their synergistic and multifunctional attributes when sterilizing different materials contaminated with a wide range of microorganisms.

Garcinia cambogia Phenolics as Potent Anti-COVID-19 Agents: Phytochemical Profiling, Biological Activities, and Molecular Docking.

COVID-19 is a disease caused by the coronavirus SARS-CoV-2 and became a pandemic in a critically short time. Phenolic secondary metabolites attracted much attention from the pharmaceutical industries for their easily accessible natural sources and proven antiviral activity. In our mission, a metabolomics study of the Garcinia cambogia Roxb. fruit rind was performed using LC-HRESIMS to investigate its chemical profile, especially the polar aspects, followed by a detailed phytochemical analysis, which led to the isolation of eight known compounds. Using spectrometric techniques, the isolated compounds were identified as quercetin, amentoflavone, vitexin, rutin, naringin, catechin, p-coumaric, and gallic acids. The antiviral activities of the isolated compounds were investigated using two assays; the 3CL-Mpro enzyme showed that naringin had a potent effect with IC50 16.62 µg/mL, followed by catechin and gallic acid (IC50 26.2, 30.35 µg/mL, respectively), while the direct antiviral inhibition effect of naringin confirmed the potency with an EC50 of 0.0169 µM. To show the molecular interaction, in situ molecular docking was carried out using a COVID-19 protease enzyme. Both biological effects and docking studies showed the hydrophobic interactions with Gln 189 or Glu 166, per the predicated binding pose of the isolated naringin.

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.

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.

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.

Scaffold Hopping of α-Rubromycin Enables Direct Access to FDA-Approved Cromoglicic Acid as a SARS-CoV-2 MPro Inhibitor.

The COVID-19 pandemic is still active around the globe despite the newly introduced vaccines. Hence, finding effective medications or repurposing available ones could offer great help during this serious situation. During our anti-COVID-19 investigation of microbial natural products (MNPs), we came across α-rubromycin, an antibiotic derived from Streptomyces collinus ATCC19743, which was able to suppress the catalytic activity (IC50 = 5.4 µM and Ki = 3.22 µM) of one of the viral key enzymes (i.e., MPro). However, it showed high cytotoxicity toward normal human fibroblasts (CC50 = 16.7 µM). To reduce the cytotoxicity of this microbial metabolite, we utilized a number of in silico tools (ensemble docking, molecular dynamics simulation, binding free energy calculation) to propose a novel scaffold having the main pharmacophoric features to inhibit MPro with better drug-like properties and reduced/minimal toxicity. Nevertheless, reaching this novel scaffold synthetically is a time-consuming process, particularly at this critical time. Instead, this scaffold was used as a template to explore similar molecules among the FDA-approved medications that share its main pharmacophoric features with the aid of pharmacophore-based virtual screening software. As a result, cromoglicic acid (aka cromolyn) was found to be the best hit, which, upon in vitro MPro testing, was 4.5 times more potent (IC50 = 1.1 µM and Ki = 0.68 µM) than α-rubromycin, with minimal cytotoxicity toward normal human fibroblasts (CC50 > 100 µM). This report highlights the potential of MNPs in providing unprecedented scaffolds with a wide range of therapeutic efficacy. It also revealed the importance of cheminformatics tools in speeding up the drug discovery process, which is extremely important in such a critical situation.

Olive-Derived Triterpenes Suppress SARS COV-2 Main Protease: A Promising Scaffold for Future Therapeutics.

SARS CoV-2 pandemic is still considered a global health disaster, and newly emerged variants keep growing. A number of promising vaccines have been recently developed as a protective measure; however, cost-effective treatments are also of great importance to support this critical situation. Previously, betulinic acid has shown promising antiviral activity against SARS CoV via targeting its main protease. Herein, we investigated the inhibitory potential of this compound together with three other triterpene congeners (i.e., ursolic acid, maslinic acid, and betulin) derived from olive leaves against the viral main protease (Mpro) of the currently widespread SARS CoV-2. Interestingly, betulinic, ursolic, and maslinic acids showed significant inhibitory activity (IC50 = 3.22-14.55 µM), while betulin was far less active (IC50 = 89.67 µM). A comprehensive in-silico analysis (i.e., ensemble docking, molecular dynamic simulation, and binding-free energy calculation) was then performed to describe the binding mode of these compounds with the enzyme catalytic active site and determine the main essential structural features required for their inhibitory activity. Results presented in this communication indicated that this class of compounds could be considered as a promising lead scaffold for developing cost-effective anti-SARS CoV-2 therapeutics.

Cnicin as an Anti-SARS-CoV-2: An Integrated In Silico and In Vitro Approach for the Rapid Identification of Potential COVID-19 Therapeutics.

Since the emergence of the SARS-CoV-2 pandemic in 2019, it has remained a significant global threat, especially with the newly evolved variants. Despite the presence of different COVID-19 vaccines, the discovery of proper antiviral therapeutics is an urgent necessity. Nature is considered as a historical trove for drug discovery, especially in global crises. During our efforts to discover potential anti-SARS CoV-2 natural therapeutics, screening our in-house natural products and plant crude extracts library led to the identification of C. benedictus extract as a promising candidate. To find out the main chemical constituents responsible for the extract's antiviral activity, we utilized recently reported SARS CoV-2 structural information in comprehensive in silico investigations (e.g., ensemble docking and physics-based molecular modeling). As a result, we constructed protein-protein and protein-compound interaction networks that suggest cnicin as the most promising anti-SARS CoV-2 hit that might inhibit viral multi-targets. The subsequent in vitro validation confirmed that cnicin could impede the viral replication of SARS CoV-2 in a dose-dependent manner, with an IC50 value of 1.18 µg/mL. Furthermore, drug-like property calculations strongly recommended cnicin for further in vivo and clinical experiments. The present investigation highlighted natural products as crucial and readily available sources for developing antiviral therapeutics. Additionally, it revealed the key contributions of bioinformatics and computer-aided modeling tools in accelerating the discovery rate of potential therapeutics, particularly in emergency times like the current COVID-19 pandemic.

Nature as a treasure trove of potential anti-SARS-CoV drug leads: a structural/mechanistic rationale.

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.

Microbial Natural Products as Potential Inhibitors of SARS-CoV-2 Main Protease (Mpro).

The main protease (Mpro) of the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was subjected to hyphenated pharmacophoric-based and structural-based virtual screenings using a library of microbial natural products (>24,000 compounds). Subsequent filtering of the resulted hits according to the Lipinski's rules was applied to select only the drug-like molecules. Top-scoring hits were further filtered out depending on their ability to show constant good binding affinities towards the molecular dynamic simulation (MDS)-derived enzyme's conformers. Final MDS experiments were performed on the ligand-protein complexes (compounds 1-12, Table S1) to verify their binding modes and calculate their binding free energy. Consequently, a final selection of six compounds (1-6) was proposed to possess high potential as anti-SARS-CoV-2 drug candidates. Our study provides insight into the role of the Mpro structural flexibility during interactions with the possible inhibitors and sheds light on the structure-based design of anti-coronavirus disease 2019 (COVID-19) therapeutics targeting SARS-CoV-2.