Attacking the SARS-CoV-2 Replication Machinery with the Pathogen Box's Molecules

Introduction: The world is currently facing a pandemic initiated by the new coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus. Viral transcription and replication are the fundamental processes of any virus. They allow the synthesis of genetic material and the consequent multiplication of the virus to infect other cells or organisms.Methods: The most important protein in SARS-CoV-2 is the RNA polymerase (RdRp or nsp12), responsible for both processes. The structure of this protein (PDB ID: 6M71) was used as a target in the application of computational strategies for a drug search, like virtual screening and molecular docking. Here, the Pathogen Box database of chemical compounds was used together with Remdesivir, Beclabuvir, and Sofosbuvir drugs as potential inhibitors of nsp12.Results: The results showed Top10 potential target inhibitors with binding energy (ΔG) higher than those of the positive controls, of which TCMDC-134153 and TCMDC-135052, both with ΔG = −7.53 kcal/mol, present interactions with three important residues of the nsp12 catalytic site.Conclusion: These proposed ligands would be used for subsequent validation by molecular dynamics, where they can be considered as drugs for the development of effective treatments against this new pandemic.

On Analysis of Temperature Based Topological Indices of Some Covid-19 Drugs

A variety of graphical invariants have been described and tested, offering lots of applications in the fields of nanochemistry, computational networks and in different scientific research areas. One commonly studied group of invariants is the topological index, which allows to research the chemical, biological, and physical properties of a chemical structure. Topological indexes are numerical quantities that can be used to describe the properties of the molecular graph. In this article, we draw from the analytically closed formulas of certain molecular structures of coronavirus such as Ribavirin, Sofosbuvir and Oseltamivir by calculating temperature based topological indices.

QSPR Study and Distance-Based New Topological Descriptors of Some Drugs Used in the COVID-19 Treatment

In chemistry and medical sciences, it is essential to study the chemical, biological, clinical, and therapeutic aspects of pharmaceuticals. To save time and money, mathematical chemistry focuses on topological indices used in quantitative structure-property relationship (QSPR) models to predict the properties of chemical structures. The COVID-19 pandemic is widely recognized as the greatest life-threatening crisis facing modern medicine. Scientists have tested various antiviral drugs available to treat COVID-19 disease, and some have found that they help get rid of this viral infection. Antiviral drugs such as Arbidol, chloroquine, hydroxychloroquine, lopinavir, remdesivir, ritonavir, thalidomide, and theaflavin are used to treat COVID-19. In this paper, reformulated leap Zagreb indices are introduced. Then, the reformulated leap Zagreb indices, leap eccentric connectivity indices, and reformulated Zagreb connectivity indices of these antiviral drugs are calculated. Curvilinear and multilinear regression models predicting the physicochemical properties of these antiviral drugs in terms of proposed indices are obtained and analyzed. The findings and models of this study will shed light on new drug discoveries for the treatment of COVID-19.

Topological Study of Some Covid-19 Drugs by Using Temperature Indices

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) was identified in December (2019) as the cause of an outbreak of a respiratory sickness and has infected more than 190 million people all over the world. Numerous vaccines have been tested for corona virus (Covid-19) therapy such as Hydoxychloroquine, Ribavirin, sofosbuvir, tenofuvir and remdisivir. Hydroxychloroquine (HCQ), which is used in the treatment of malaria or treat infection, has recently been demonstrated for use in COVID-19 as an emergency therapy. The chemical substance HCQ is manufactured by rearranging the molecular structure of Ethylene oxide produced by human products, such as waxy maize starch. In medical science chemical properties, physical properties, pharmaceutical properties and biological properties of medicines are essential for designing of the drugs. These properties can be identified by topological indices. In this paper, we compute the temperature based topological indices of hydroxychoroquine HCQ-HES, and the discoveries will be beneficial in the development of novel drugs and vaccines in order to avoid and operation of corona virus (COVID-19). [ABSTRACT FROM AUTHOR] Copyright of Polycyclic Aromatic Compounds is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Thermal Assessment of a Ventilated Double Skin Façade Component with a Set of Air Filtering Photocatalytic Slats in the Cavity

Indoor air quality is a crucial factor when evaluating habitability, especially in developed countries, where people spend most of their time indoors. This paper presents a novel double skin façade (DSF) system that combines physical and photocatalytic filtering strategies. The air purification system is made up of fixed slats that are both solar protection and air purification system. The objective of this work is to determine the thermal behaviour of the proposed system, so that its suitability for use in various environments may be assessed. This was carried out using a physical 1:1 scale model and a computational fluid dynamics (CFD) model. The maximum temperature inside the scale model cavity was 17–20 °C higher than outdoor air. Additionally, it was discovered that the airflow through the DSF would require forced ventilation. To determine the emissivity values of the photocatalytic coating, additional experimental measurements were made. The CFD model was tested for summer and winter conditions in Barcelona, Chicago, and Vancouver. The average increase in the intake air temperature was around 14.5 °C in winter and 12 °C in summer, finding that the system has its main use potential in temperate or cold areas with many hours of solar radiation.

EMPHASIZING SOME CHARACTERISTICS OF NATURAL SALTED WATERS' AREAS, USED FOR PUBLIC HEALTH IMPROVEMENT

In recent years, more and more data has become available about the benefits of green in and around cities. Vegetation helps people to recover faster from illness;this reduces costs of healthcare and improves the patients ' quality of life. In highly urbanized locations, the design of green elements requires special attention. Our paper presents a multidisciplinary study of areas located near the old salt mines and their use by entering in the spa and leisure circuit. Specific components were monitored, like the salted waters quality in lakes and/or springs and the identification of different plant species adapted to high salinity of the soil and able to enrich a green zone. In recent years, the continuous degradation of environmental quality due to factors such as air pollution, noise, chemical compounds, the pandemic state due to COVID-19 and disappearance of natural areas, in combination with lifestyle changes led to the emergence of a growing number of diseases such as different forms of diabetes, cardiovascular and nervous system disorders and cancer.

A molecular dynamic investigation of human rhinovirus 3c protease drug target: insights towards the design of potential inhibitors

The 3C protease is distinguished from most proteases due to the presence of cysteine nucleophile that plays an essential role in viral replication. This peculiar structure encompassed with its role in viral replication has promoted 3C protease as an interesting target for therapeutic agents in the treatment of diseases caused by human rhinovirus (HRV). However, the molecular mechanisms surrounding the chirality of inhibitors of HRV 3C protease remain unresolved. Herein using in silico techniques such molecular dynamic simulation and binding free estimations via molecular mechanics poisson-boltzmann surface area (MM/PBSA), we present a comprehensive molecular dynamics study of the comparison of two potent inhibitors, SG85 and rupintrivir, complexed with HRV3C protease. The binding free energy studies revealed a higher binding affinity for SG85 of 58.853 kcal/mol than that for rupintrivir of 54.0873 kcal/mol and this was found to be in correlation with the experimental data. The energy decomposition analysis showed that residues Leu 127, Thr 142, Ser 144, Gly 145, Tyr 146, Cys 147, His 161, Val 162, Gly 163, Gly 164, Asn 165, and Phe 170 largely contributed to the binding of SG85, whereas His 40, Leu 127, and Gly 163 impacted the binding of rupintrivir. The results further showed that His 40, Glu 71, Leu 127, Cys 147, Gly 163, and Gyl 164 were crucial residues that played a key role in ligand-enzyme binding, and amongst these crucial residues, His 40, Glu 71, and Cys 147 appeared to be conserved in the active site of HRV-3C protease when bound by both inhibitors. These findings provided a comprehensive understanding of the dynamics and structural features and would serve as guidance in the design and development of potent novel inhibitors of HRV.

Plant Exosomal Vesicles: Perspective Information Nanocarriers in Biomedicine

Exosomal nanoparticles (exosomes or nanovesicles) are biogenic membrane vesicles secreted by various cell types and represent a conservative mechanism of intercellular and interspecies communication in pro- and eukaryotic organisms. By transporting specific proteins, nucleic acids, and low molecular weight metabolites, the exosomes are involved in the regulation of developmental processes, activation of the immune system, and the development of a protective response to stress. Recently, the plant nanovesicles, due to an economical and affordable source of their production, have attracted a lot of attention in the biomedical field. Being a natural transport system, the plant exosomes represent a promising platform in biomedicine for the delivery of molecules of both endogenous and exogenous origin. This review presents current data on the biogenesis of plant exosomes and their composition, as well as mechanisms of their loading with various therapeutic compounds, which are determining factors for their possible practical use. We believe that further research in this area will significantly expand the potential of targeted therapy, particularly targeted gene regulation via the small RNAs, due to the use of plant exosomes in clinical practice.

Ve-Degree, Ev-Degree, and Degree-Based Topological Indices of Fenofibrate

The molecular topology of a graph is described by topological indices, which are numerical measures. In theoretical chemistry, topological indices are numerical quantities that are used to represent the molecular topology of networks. These topological indices can be used to calculate several physical and chemical properties of chemical compounds, such as boiling point, entropy, heat generation, and vaporization enthalpy. Graph theory comes in handy when looking at the link between certain topological indices of some derived graphs. In the ongoing research, we determine ve-degree, ev-degree, and degree-based (D-based) topological indices of fenofibrate’s chemical structure. These topological indices are the Zagreb index, general Randić index, modified Zagreb index, and forgotten topological index. These indices are very helpful to study the characterization of the given structure.

On Reverse Valency Based Topological Characterization of a Chemical Compound

Metal-organic frameworks explicit the consequence of these frameworks with adjustable implementations, namely, energy storage gadgets of magnificent electrode materials, gas store, heterogeneous catalysis, environmental hazard, estimation of chemicals, recognizing of definite gases, controlling solids, and supercapacitors. In this paper, we give explicit expression of the reverse general Randic index, the reverse atom bond connectivity index, the reverse geometric arithmetic index, the reverse forgotten index, the reverse Balaban index, the reverse augmented index, and different types of reverse Zagreb indices of the metal-organic framework M1TPyP-M2 (TPyP = 5, 10, 15, 20-tetrakis (4-pyridyl) porphyrin and M1, M2 = Fe and Co). A graphical comparison of the calculated different types of the reverse degree based topological indices with the aid of the numerical values is also included.

Use of the Genus Satureja as Food Supplement: Possible Modulation of the Immune System via Intestinal Microbiota During SARS-CoV-2 Infection

Satureja genus belongs to the Lamiaceae family, and they are used in food products and by pharmaceutical and cosmetic industries. The chemical composition of Satureja is responsible for its pharmacological and phytochemical properties. Among the various biological activities, notably antioxidant, antibacterial and antifungal, Satureja also has a potential antiviral activity. The existence of a microbiota modulation potential by Satureja in farming animals has also been reported. Viral pathologies are one of the main causes of disease in the world. It is commonly known that gut microbiota plays a crucial role in the fight and progression of viral infection. Previous studies conducted on coronavirus disease 2019 (COVID-19) pandemic have proved an imbalance in the intestinal and pulmonary microbiota via gut-lung axis. Knowing the properties of Satureja and its traditional use, one can suggest the possibility of using it as dietary supplement to modulate immune system in order to prevent and fight viral infections. The objective of this review is to reveal the potential impact of medicinal plants such as Satureja genus as a food supplement, on immune enhancing during SARS-CoV-2 infection and their relationships with the intestinal microbiota.

Chemical Compounds and Antimicrobial Activities of Actinomycetes Isolates from BRIS Soil

The existing study examined three actinomycetes isolated from Beach Ridges Interspersed with Swales (BRIS) soil where the morphological properties were examined and chemical compounds of their metabolite extracts were ana;ysed. Based on phylogenetic analysis of 16S rRNA gene sequences, the strains were identified as Streptomyces sp. AA13, Amycolatopsis sp. AA12 and Micromonosporasp. AA141. Antimicrobial activities of the extracts were tested against a panel of microorganisms that consist of Escherichia coli DSM 30083, Bacillus subtilis DSM 10, Pseudomonas fluorescens DSM 50090, Klebsiella pneumoniae DSM 30104, Micrococcus luteus DSM 20030, and Saccharomyces cerevisiae. Results revealed a wide range of antimicrobial activities produced by the isolates at different concentration of each extracts. The extracts were found to show stronger antimicrobial activities against gram-negative bacteria compared to gram-positive bacteria, while no activities were shown when tested against fungi. Thirty-nine compounds were detected both from Streptomycessp. AA13 and Amycolatopsissp. AA12, while thirty-eight compounds from Micromonosporasp. AA141 using GC-MS. This Study Demonstrate the ability of actinomycetes in producing variety type of compounds with antimicrobial activities that may be the potential candidates as drug leads.

Can Extracts from the Leaves and Fruits of the Cotoneaster Species Be Considered Promising Anti-Acne Agents?

This study aimed to evaluate the phenolic profile and biological activity of the extracts from the leaves and fruits of Cotoneaster nebrodensis and Cotoneaster roseus. Considering that miscellaneous species of Cotoneaster are thought to be healing in traditional Asian medicine, we assumed that this uninvestigated species may reveal significant therapeutic properties. Here, we report the simultaneous assessment of chemical composition as well as biological activities (antioxidant, anti-inflammatory, antibacterial, and cytotoxic properties) of tested species. Complementary LC-MS analysis revealed that polyphenols (especially flavonoids and proanthocyanidins) are the overriding phytochemicals with the greatest significance in tested biological activities. In vitro chemical tests considering biological activities revealed that obtained results showed different values depending on concentration, extraction solvent as well as phenolic content. Biological assays demonstrated that the investigated extracts possessed antibacterial properties and were not cytotoxic toward normal skin fibroblasts. Given the obtained results, we concluded that knowledge of the chemical composition and biological activities of investigated species are important to achieve a better understanding of the utilization of these plants in traditional medicine and be useful for further research in their application to treat various diseases, such as skin disorders.

Chemical Characterization of Taif Rose (Rosa damascena Mill var. trigentipetala) Waste Methanolic Extract and Its Hepatoprotective and Antioxidant Effects against Cadmium Chloride (CdCl2)-Induced Hepatotoxicity and Potential Anticancer Activities against Liver Cancer Cells (HepG2)

Taif rose (Rosa damascena Mill) is one of the most important economic products of the Taif Governorate, Saudi Arabia. Cadmium chloride (CdCl2) is a common environmental pollutant that is widely used in industries and essentially induces many toxicities, including hepatotoxicity. In this study, the major compounds in the waste of Taif rose extract (WTR) were identified and chemically and biologically evaluated. GC–MS analysis of WTR indicated the presence of many saturated fatty acids, vitamin E, triterpene, dicarboxylic acid, terpene, linoleic acid, diterpenoid, monoterpenoid, flavonoids, phenylpyrazoles, and calcifediol (vitamin D derivative). The assessment of potential anticancer activity against HepG2 cells proved that WTR had a high cell killing effect with IC50 of 100–150 µg/mL. In addition, WTR successfully induced high cell cycle arrest at G0/G1, S, and G2 phases, significant apoptosis, necrosis, and increased autophagic cell death response in the HepG2 line. For the evaluation of its anti-CdCl2 toxicity, 32 male rats were allocated to four groups: control, CdCl2, WTR, and CdCl2 plus WTR. Hepatic functions and antioxidant biomarkers (SOD, CAT, GRx, GPx, and MDA) were examined. Histological changes and TEM variations in the liver were also investigated to indicate liver status. The results proved that WTR alleviated CdCl2 hepatotoxicity by improving all hepatic vitality markers. In conclusion, WTR could be used as a preventive and therapeutic natural agent for the inhibition of hepatic diseases and the improvement of redox status. Additional in vitro and in vivo studies are warranted.

Chemical and chemoenzymatic stereoselective synthesis of β-nucleosides and their analogues

β-Nucleosides are fundamental building blocks of biological systems and are widely used as therapeutic agents for the treatment of cancer and viral infections, among others. In the last two years, nucleoside analogues have been investigated with renewed urgency in the search for agents that are effective against SARS-CoV-2, the cause of the ongoing global pandemic of COVID-19. This has resulted in an explosion of activities in the field of β-nucleoside synthesis. This review summarizes the historical perspective and the recent advances in the stereoselective synthesis of β-nucleosides and their analogues. The synthetic strategies to obtain β-nucleosides can be divided into three categories: (1) N-glycosylation;(2) intramolecular sugar ring formation;and (3) enzymatic transglycosylation.

Dysregulation of the PACT-mediated Crosstalk Between Protein Kinases PKR and PERK Contributes to Dystonia 16 (DYT16)

Currently, the available treatment options for dystonia are merely palliative and the drug development has not progressed significantly due to a lack of understanding about the involved molecular pathomechanisms. We investigated if PACT, the gene mutated in dystonia 16 (DYT16), causes a disruption in the normal regulatory crosstalk between PERK and PKR kinases leading to a loss of cell homeostasis after ER stress. Both PERK and PKR kinases phosphorylate eIF2 alpha and activate a downstream signaling pathway that allows recovery and survival after ER stress. The most significant finding during the last funding period was that PACT is a substrate of PERK kinase and PERK phosphorylates PACT in vivo after ER stress. This is a paradigm-shifting finding as it was previously unknown that PACT could participate and regulate both PKR and PERK pathways. The molecular etiology of DYT16 has now been conclusively shown to be a dysregulation of eIF2 alpha signaling. Thus, our research has uncovered a PACT-mediated novel regulatory pathway and laid the foundation for more in depth drug development to target PACT-PERKinteractions in future. In addition, it has added significant new knowledge about how cells respond to ER stress. In the brief period of 8 months we made significant progress included in this report, before the COVID-19 pandemic slowed down our work significantly.

The Current Directions of Searching for Antiparasitic Drugs.

Parasitic diseases are still a huge problem for mankind. They are becoming the main cause of chronic diseases in the world. Migration of the population, pollution of the natural environment, and climate changes cause the rapid spread of diseases. Additionally, a growing resistance of parasites to drugs is observed. Many research groups are looking for effective antiparasitic drugs with low side effects. In this work, we present the current trends in the search for antiparasitic drugs. We report known drugs used in other disease entities with proven antiparasitic activity and research on new chemical structures that may be potential drugs in parasitic diseases. The described investigations of antiparasitic compounds can be helpful for further drug development.

A Dual‐Color Fluorescent Probe Allows Simultaneous Imaging of Main and Papain‐like Proteases of SARS‐CoV‐2‐Infected Cells for Accurate Detection and Rapid Inhibitor Screening

The main protease (Mpro) and papain‐like protease (PLpro) play critical roles in SARS‐CoV‐2 replication and are promising targets for antiviral inhibitors. The simultaneous visualization of Mpro and PLpro is extremely valuable for SARS‐CoV‐2 detection and rapid inhibitor screening. However, such a crucial investigation has remained challenging because of the lack of suitable probes. We have now developed a dual‐color probe (3MBP5) for the simultaneous detection of Mpro and PLpro by fluorescence (or Förster) resonance energy transfer (FRET). This probe produces fluorescence from both the Cy3 and Cy5 fluorophores that are cleaved by Mpro and PLpro. 3MBP5‐activatable specificity was demonstrated with recombinant proteins, inhibitors, plasmid‐transfected HEK 293T cells, and SARS‐CoV‐2‐infected TMPRSS2‐Vero cells. Results from the dual‐color probe first verified the simultaneous detection and intracellular distribution of SARS‐CoV‐2 Mpro and PLpro. This is a powerful tool for the simultaneous detection of different proteases with value for the rapid screening of inhibitors.

Anti-inflammatory potential of λ-carrageenan by inhibition of IL-6 receptor: in silico study

In some cases, the immune system in COVID-19 patients leads to the release of excess cytokine production (cytokine storm), which will potentially develop into pneumonia. Interleukin 6 (IL-6) plays the role of pro-inflammatory cytokine, it is a receptor mediated signalling system. Macroalgae is well known as a source of valuable bioactive substances with potential biological activities. Among them is the sulphated polysaccharide lambda-carrageenan λ-CGN which has been reported as an anti-inflammatory agent. However, its mechanism of action against IL-6 production is currently unknown. This study aims to predict potential molecular mechanisms of λ-CGN chemical compound against IL-6 expression through in silico study. Chemical compound of λ-CGN and target protein in this study were obtained from the pubchem and protein data bank (PDB). The molecular docking prediction was conducted with PyRx software, the result is λ-CGN compound showing strong binding energy to bind target protein IL-6 receptor with the value of -5.9 kcal/mol. Based on the results of in silico study, the sulphated polysaccharide λ-CGN potentially inhibits IL-6R expression by binding ligand pocket with six conventional hydrogen bonds (amino acid residus: His256, His 257, Trp 219, Arg 231, and Asp 221) and two carbon hydrogen bonds (amino acid residus: THR 218 and GLN 220). Binding with these amino acid residues potentially contributes to IL-6 receptor structural change which could result in functional change. Hence, further studies related to in vitro and in vivo investigations would be interesting to further understand the inhibitory mechanism of λ-CGN against IL-6.

Anti-malarial drug, artemisinin and its derivatives for the treatment of respiratory diseases.

Artemisinins are sesquiterpene lactones with a peroxide moiety that are isolated from the herb Artemisia annua. It has been used for centuries for the treatment of fever and chills, and has been recently approved for the treatment of malaria due to its endoperoxidase properties. Progressively, research has found that artemisinins displayed multiple pharmacological actions against inflammation, viral infections, and cell and tumour proliferation, making it effective against diseases. Moreover, it has displayed a relatively safe toxicity profile. The use of artemisinins against different respiratory diseases has been investigated in lung cancer models and inflammatory-driven respiratory disorders. These studies revealed the ability of artemisinins in attenuating proliferation, inflammation, invasion, and metastasis, and in inducing apoptosis. Artemisinins can regulate the expression of pro-inflammatory cytokines, nuclear factor-kappa B (NF-κB), matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), promote cell cycle arrest, drive reactive oxygen species (ROS) production and induce Bak or Bax-dependent or independent apoptosis. In this review, we aim to provide a comprehensive update of the current knowledge of the effects of artemisinins in relation to respiratory diseases to identify gaps that need to be filled in the course of repurposing artemisinins for the treatment of respiratory diseases. In addition, we postulate whether artemisinins can also be repurposed for the treatment of COVID-19 given its anti-viral and anti-inflammatory properties.