Computational study of novel inhibitory molecule, 1-(4-((2S,3S)-3-amino-2-hydroxy-4-phenylbutyl)piperazin-1-yl)-3-phenylurea, with high potential to competitively block ATP binding to the RNA dependent RNA polymerase of SARS-CoV-2 virus.

For coronaviruses, RNA-dependent RNA polymerase (RdRp) is an essential enzyme that catalyses the replication from RNA template and therefore remains an attractive therapeutic target for anti-COVID drug discovery. In the present study, we performed a comprehensive in silico screening for 16,776 potential molecules from recently established drug libraries based on two important pharmacophores (3-amino-4-phenylbutan-2-ol and piperazine). Based on initial assessment, 4042 molecules were obtained suitable as drug candidates, which were following Lipinski's rule. Molecular docking implemented for the analysis of molecular interactions narrowed this number of compounds down to 19. Subsequent to screening filtering criteria and considering the critical parameters viz. docking score and MM-GBSA binding free energy, 1-(4-((2S,3S)-3-amino-2-hydroxy-4-phenylbutyl)piperazin-1-yl)-3-phenylurea (compound 1) was accomplished to score highest in comparison to the remaining 18 shortlisted drug candidates. Notably, compound 1 displayed higher docking score (-8.069 kcal/mol) and MM-GBSA binding free energy (-49.56 kcal/mol) than the control drug, remdesivir triphosphate, the active form of remdesivir as well as adenosine triphosphate. Furthermore, a molecular dynamics simulation was carried out (100 ns), which substantiated the candidacy of compound 1 as better inhibitor. Overall, our systematic in silico study predicts the potential of compound 1 to exhibit a more favourable specific activity than remdesivir triphosphate. Hence, we suggest compound 1 as a novel potential drug candidate, which should be considered for further exploration and validation of its potential against SARS-CoV-2 in wet lab experimental studies.Communicated by Ramasawamy H. Sarma.

Natural Products as Anti-COVID-19 Agents: An In Silico Study

Background: The coronavirus disease 2019 (COVID-19) is a life-threatening viral infection caused by a positive-strand RNA virus belonging to the Coronaviridae family called severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2). This virus has infected millions of peo-ples and caused hundreds of thousands of deaths around the world. Unfortunately, to date, there is no specific cure for SARS-CoV-2 infection, although researchers are working tirelessly to come up with a drug against this virus. Recently, the main viral protease has been discovered and is regarded as an ap-propriate target for antiviral agents in the search for the treatment of SARS-CoV-2 infection due to its role in polyproteins processing coronavirus replication. Material(s) and Method(s): This investigation (an in silico study) explores the effectiveness of 16 natural compounds from a literature survey against the protease of SARS-CoV-2 in an attempt to identify a promising antiviral agent through a molecular docking study. Result(s): Among the 16 compounds studied, apigenin, alpha-hederin, and asiatic acid exhibited significant docking performance and interacted with several amino acid residues of the main protease of SARS-CoV-2. Conclusion(s): In summary, apigenin, alpha-hederin, and asiatic acid protease inhibitors may be effective potential antiviral agents against the main viral protease (Mpro) to combat SARS-CoV-2.Copyright © 2021 Bentham Science Publishers.

Combined in silico strategy for repurposing DrugBank entries towards introducing potential anti-SARS-CoV-2 drugs.

The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) from China in December 2019 led to the coronavirus disorder 2019 pandemic, which has affected tens of millions of humans worldwide. Various in silico research via bio-cheminformatics methods were performed to examine the efficiency of a range of repurposed approved drugs with a new role as anti-SARS-CoV-2 drugs. The current study has been performed to screen the approved drugs in the DrugBank database based on a novel bioinformatics/cheminformatics strategy to repurpose available approved drugs towards introducing them as a possible anti-SARS-CoV-2 drug. As a result, 96 approved drugs with the best docking scores passed through several relevant filters were presented as the candidate drugs with potential novel antiviral activities against the SARS-CoV-2 virus.

In silico screening of potential antiviral inhibitors against SARS-CoV-2 main protease

Respiratory illness due to SARS-CoV-2 emerged in 2019 and has a significant morbidity and mortality rate. The main protease (Mpro) is mainly responsible for viral replications, which acts as a good drug target to inhibit SARS-CoV-2-related diseases. Chemical compounds obtained from various herbal plants are showing potent antiviral activity against numerous viral diseases. Initial screening was performed with the phytochemicals against Mpro using molecular docking. This result shows that there is a strong interaction exhibited between active sites (His-41 and Cys-145) of Mpro with chemical compounds. In addition, ADME prediction and Lipinski's rule of five (RO5) calculations demonstrated that the selected compounds have potential drug-like properties. Further, molecular dynamics (MD) simulations were performed to understand the stability and structural changes of protein–ligand complexes for the top five compounds. MM/PBSA studies strongly suggested that compounds, β-spinasterol, and asarinin form stable complexes with Mpro. The most significant hot spot residues such as Thr-25, Met-49, Cys-145, Met-165, and Gln-189 have strongly interacted with the selected chemical compounds. Our calculations suggest that asarinin is the best inhibitor to the Mpro, which supports these candidates and could be potent antiviral agent against SARS-CoV-2. © 2022 Informa UK Limited, trading as Taylor & Francis Group.

Repurposing of chemotherapeutics to combat COVID-19.

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is a novel strain of SARS coronavirus. The COVID-19 disease caused by this virus was declared a pandemic by the World Health Organization (WHO). SARS-CoV-2 mainly spreads through droplets sprayed by coughs or sneezes of the infected to a healthy person within the vicinity of 6 feet. It also spreads through asymptomatic carriers and has negative impact on the global economy, security and lives of people since 2019. Numerous lives have been lost to this viral infection; hence there is an emergency to build up a potent measure to combat SARS-CoV-2. In view of the non-availability of any drugs or vaccines at the time of its eruption, the existing antivirals, antibacterials, antimalarials, mucolytic agents and antipyretic paracetamol were used to treat the COVID-19 patients. Still there are no specific small molecule chemotherapeutics available to combat COVID-19 except for a few vaccines approved for emergency use only. Thus, the repurposing of chemotherapeutics with the potential to treat COVID-19 infected people is being used. The antiviral activity for COVID-19 and biochemical mechanisms of the repurposed drugs are being explored by the biological assay screening and structure-based in silico docking simulations. The present study describes the various US-FDA approved chemotherapeutics repositioned to combat COVID-19 along with their screening for biological activity, pharmacokinetic and pharmacodynamic evaluation.

Benchmarked molecular docking integrated molecular dynamics stability analysis for prediction of SARS-CoV-2 papain-like protease inhibition by olive secoiridoids.

Objectives: We performed a virtual screening of olive secoiridoids of the OliveNetTM library to predict SARS-CoV-2 PLpro inhibition. Benchmarked molecular docking protocol that evaluated the performance of two docking programs was applied to execute virtual screening. Molecular dynamics stability analysis of the top-ranked olive secoiridoid docked to PLpro was also carried out. Methods: Benchmarking virtual screening used two freely available docking programs, AutoDock Vina 1.1.2. and AutoDock 4.2.1. for molecular docking of olive secoiridoids to a single PLpro structure. Screening also included benchmark structures of known active and decoy molecules from the DEKOIS 2.0 library. Based on the predicted binding energies, the docking programs ranked the screened molecules. We applied the usual performance evaluation metrices to evaluate the docking programs using the predicted ranks. Molecular dynamics of the top-ranked olive secoiridoid bound to PLpro and computation of MM-GBSA energy using three iterations during the last 50 ps of the analysis of the dynamics in Desmond supported the stability prediction. Results and discussions: Predictiveness curves suggested that AutoDock Vina has a better predictive ability than AutoDock, although there was a moderate correlation between the active molecules rankings (Kendall's correlation of rank (τ) = 0.581). Interestingly, two same molecules, Demethyloleuropein aglycone, and Oleuroside enriched the top 1 % ranked olive secoiridoids predicted by both programs. Demethyloleuropein aglycone bound to PLpro obtained by docking in AutoDock Vina when analyzed for stability by molecular dynamics simulation for 50 ns displayed an RMSD, RMSF<2 Å, and MM-GBSA energy of -94.54 ± 6.05 kcal/mol indicating good stability. Molecular dynamics also revealed the interactions of Demethyloleuropein aglycone with binding sites 2 and 3 of PLpro, suggesting a potent inhibition. In addition, for 98 % of the simulation time, two phenolic hydroxy groups of Demethyloleuropein aglycone maintained two hydrogen bonds with Asp302 of PLpro, specifying the significance of the groups in receptor binding. Conclusion: AutoDock Vina retrieved the active molecules accurately and predicted Demethyloleuropein aglycone as the best inhibitor of PLpro. The Arabian diet consisting of olive products rich in secoiridoids benefits from the PLpro inhibition property and reduces the risk of viral infection.

Repurposing of potential antiviral drugs against RNA-dependent RNA polymerase of SARS-CoV-2 by computational approach.

The high incidences of COVID-19 cases are believed to be associated with high transmissibility rates, which emphasizes the need for the discovery of evidence-based antiviral therapies for curing the disease. The rationale of repurposing existing classes of antiviral small molecule therapeutics against SARS-CoV-2 infection has been expected to accelerate the tedious and expensive drug development process. While Remdesivir has been recently approved to be the first treatment option for specific groups of COVID-19 patients, combinatory therapy with potential antiviral drugs may be necessary to enhance the efficacy in different populations. Hence, a comprehensive list of investigational antimicrobial drug compounds such as Favipiravir, Fidaxomicin, Galidesivir, GC376, Ribavirin, Rifabutin, and Umifenovir were computationally evaluated in this study. We performed in silico docking and molecular dynamics simulation on the selected small molecules against RNA-dependent RNA polymerase, which is one of the key target proteins of SARS-CoV-2, using AutoDock and GROMACS. Interestingly, our results revealed that the macrocyclic antibiotic, Fidaxomicin, possesses the highest binding affinity with the lowest energy value of -8.97 kcal/mol binding to the same active sites of RdRp. GC376, Rifabutin, Umifenovir and Remdesivir were identified as the next best compounds. Therefore, the above-mentioned compounds could be considered good leads for further preclinical and clinical experimentations as potentially efficient antiviral inhibitors for combination therapies against SARS-CoV-2.

Exploration of chalcones as 3-chymotrypsin-like protease (3CLpro) inhibitors of SARS-CoV-2 using computational approaches.

The main protease 3CLpro is one of the potential targets against coronavirus. Inhibiting this enzyme leads to the interruption of viral replication. Chalcone and its derivatives were reported to possess the ability to bind to 3CLpro protease in the binding pocket. This study explored an in-house database of 269 chalcones as 3CLpro inhibitors using in silico screening models, including molecular docking, molecular dynamics simulation, binding free energy calculation, and ADME prediction. C264 and C235 stand out as the two most potential structures. The top hit compound C264 was with the Jamda score of -2.8329 and the MM/GBSA binding energy mean value of -28.23 ± 3.53 kcal/mol, which was lower than the reference ligand. Despite the lower mean binding energy (-22.07 ± 3.39 kcal/mol), in-depth analysis of binding interaction suggested C235 could be another potential candidate. Further, in vitro and in vivo experiments are required to confirm the inhibitory ability. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02000-3.

Discovery of Natural Lead Compound from Dendrobium sp. against SARS-CoV-2 Infection.

Since the pandemic of severe acute respiratory syndrome coronavirus (SARS-CoV-2) in December 2019, the infection cases have quickly increased by more than 511 million people. The long epidemic outbreak over 28 months has affected health and economies worldwide. An alternative medicine appears to be one choice to alleviate symptoms and reduce mortality during drug shortages. Dendrobium extract is one of the traditional medicines used for COVID-19 infection. Several compounds in Dendrobium sp. had been reported to exert pharmacological activities to treat common COVID-19-related symptoms. Herein, in silico screening of 83 compounds from Dendrobium sp. by using the SARS-CoV-2 spike protein receptor-binding domain (RBD) as a drug target was performed in searching for a new lead compound against SARS-CoV-2 infection. Four hit compounds showing good binding affinity were evaluated for antiviral infection activity. The new lead compound DB36, 5-methoxy-7-hydroxy-9,10-dihydro-1,4-phenanthrenequinone, was identified with the IC50 value of 6.87 ± 3.07 µM. The binding mode revealed that DB36 bound with the spike protein at the host receptor, angiotensin-converting enzyme 2 (ACE2) binding motif, resulted in antiviral activity. This study substantiated the use of Dendrobium extract for the treatment of SARS-CoV-2 infection and has identified new potential chemical scaffolds for further drug development of SARS-CoV-2 entry inhibitors.

In Silico Screening and Testing of FDA-Approved Small Molecules to Block SARS-CoV-2 Entry to the Host Cell by Inhibiting Spike Protein Cleavage.

The COVID-19 pandemic began in 2019, but it is still active. The development of an effective vaccine reduced the number of deaths; however, a treatment is still needed. Here, we aimed to inhibit viral entry to the host cell by inhibiting spike (S) protein cleavage by several proteases. We developed a computational pipeline to repurpose FDA-approved drugs to inhibit protease activity and thus prevent S protein cleavage. We tested some of our drug candidates and demonstrated a decrease in protease activity. We believe our pipeline will be beneficial in identifying a drug regimen for COVID-19 patients.

From Traditional Ethnopharmacology to Modern Natural Drug Discovery: A Methodology Discussion and Specific Examples.

Ethnopharmacology, through the description of the beneficial effects of plants, has provided an early framework for the therapeutic use of natural compounds. Natural products, either in their native form or after crude extraction of their active ingredients, have long been used by different populations and explored as invaluable sources for drug design. The transition from traditional ethnopharmacology to drug discovery has followed a straightforward path, assisted by the evolution of isolation and characterization methods, the increase in computational power, and the development of specific chemoinformatic methods. The deriving extensive exploitation of the natural product chemical space has led to the discovery of novel compounds with pharmaceutical properties, although this was not followed by an analogous increase in novel drugs. In this work, we discuss the evolution of ideas and methods, from traditional ethnopharmacology to in silico drug discovery, applied to natural products. We point out that, in the past, the starting point was the plant itself, identified by sustained ethnopharmacological research, with the active compound deriving after extensive analysis and testing. In contrast, in recent years, the active substance has been pinpointed by computational methods (in silico docking and molecular dynamics, network pharmacology), followed by the identification of the plant(s) containing the active ingredient, identified by existing or putative ethnopharmacological information. We further stress the potential pitfalls of recent in silico methods and discuss the absolute need for in vitro and in vivo validation as an absolute requirement. Finally, we present our contribution to natural products' drug discovery by discussing specific examples, applying the whole continuum of this rapidly evolving field. In detail, we report the isolation of novel antiviral compounds, based on natural products active against influenza and SARS-CoV-2 and novel substances active on a specific GPCR, OXER1.

Review on In Silico Methods, High-throughput Screening Techniques, and Cell Culture Based In Vitro Assays for SARS-CoV-2.

The COVID-19 outbreak caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to have high incidence and mortality rate globally. To meet the increasingly growing demand for new therapeutic drugs and vaccines, researchers are developing different diagnostic techniques focused on screening new drugs in clinical use, developing an antibody targeting a SARS-CoV-2 receptor, or interrupting infection/replication mechanisms of SARS-CoV-2. Although many prestigious research publications are addressing this subject, there is no open access platform where all experimental techniques for COVID-19 research can be seen as a whole. Many researchers have accelerated the development of in silico methods, high-throughput screening techniques, and in vitro assays. This development has played an important role in the emergence of improved, innovative strategies, including different antiviral drug development, new drug discovery protocols, combinations of approved drugs, and setting up new drug classes during the COVID-19 outbreak. Hence, the present review discusses the current literature on these modalities, including virtual in silico methods for instant ligand- and target-driven based techniques, nucleic acid amplification tests, and in vitro models based on sensitive cell cultures, tissue equivalents, organoids, and SARS-CoV-2 neutralization systems (lentiviral pseudotype, viral isolates, etc.). This pack of complementary tests informs researchers about the accurate, most relevant emerging techniques available and in vitro assays allow them to understand their strengths and limitations. This review could be a pioneer reference guide for the development of logical algorithmic approaches for new drugs and vaccine strategies against COVID-19.

In silico drug repurposing for coronavirus (COVID-19): screening known HCV drugs against the SARS-CoV-2 spike protein bound to angiotensin-converting enzyme 2 (ACE2) (6M0J).

In this study, FDA-approved HCV antiviral drugs and their structural analogues-several of them in clinical trials-were tested for their inhibitory properties toward the SARS-CoV-2 spike protein bound to angiotensin-converting enzyme 2 (6M0J) using a virtual screening approach and computational chemistry methods. The most stable structures and the corresponding binding affinities of thirteen such antiviral compounds were obtained. Frontier molecular orbital theory, global reactivity descriptors, molecular docking calculations and electrostatic potential analysis were used to hypothesize the bioactivity of these drugs against 6M0J. It is found that an increased affinity for the protein is shown by inhibitors with large compound volume, relatively higher electrophilicity index, aromatic rings and heteroatoms that participate in hydrogen bonding. Among the tested drugs, four compounds 10-13 showed excellent results-binding affinities - 11.2 to - 11.5 kcal mol-1. These four top scoring compounds may act as lead compounds for further experimental validation, clinical trials and even for the development of more potent antiviral agents against the SARS-CoV-2. Approved HCV drugs and analogues were tested for their bioactivity towards the SARS-CoV-2 (6M0J) using virtual screening, ESP and MD analysis.

VAEResTL: A Novel Generative Model for Designing Complementarity Determining Region of Antibody for SARS-CoV-2

The global impact of the COVID-19 pandemic underlines the importance of developing a competent machine learning (ML) approach that can rapidly design therapeutics and prophylactics such as antibodies/nanobodies against novel viral infections despite data shortage problems and sequence complexity. Here, we propose a novel end-to-end deep generative model based on convolutional Variational Autoencoder (VAE), Residual Neural Network (Resnet), and Transfer Learning (TL), named VAEResTL that can competently generate CDR-H3 sequences for a novel target lacking sufficient training data. We further demonstrate that our proposed method generates the third complementarity-determining region (CDR) of the heavy chain (CDR-H3) sequences for designing and developing therapeutic antibodies/nanobodies that can bind to different variants of SARS-CoV-2 despite the shortage of SARS-CoV-2 training data. The predicted CDR-H3 sequences are then screened and filtered for their developability parameters namely viscosity, clearance, solubility, stability, and immunogenicity through several in-silico steps resulting in a list of highly optimized lead candidates.

Implication of in silico studies in the search for novel inhibitors against SARS-CoV-2.

Corona Virus Disease-19 (COVID-19) is a pandemic disease mainly caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It had spread from Wuhan, China, in late 2019 and spread over 222 countries and territories all over the world. Earlier, at the very beginning of COVID-19 infection, there were no approved medicines or vaccines for combating this disease, which adversely affected a lot of individuals worldwide. Although frequent mutation leads to the generation of more deadly variants of SARS-CoV-2, researchers have developed several highly effective vaccines that were approved for emergency use by the World Health Organization (WHO), such as mRNA-1273 by Moderna, BNT162b2 by Pfizer/BioNTech, Ad26.COV2.S by Janssen, AZD1222 by Oxford/AstraZeneca, Covishield by the Serum Institute of India, BBIBP-CorV by Sinopharm, coronaVac by Sinovac, and Covaxin by Bharat Biotech, and the first US Food and Drug Administration-approved antiviral drug Veklury (remdesivir) for the treatment of COVID-19. Several waves of COVID-19 have already occurred worldwide, and good-quality vaccines and medicines should be available for ongoing as well as upcoming waves of the pandemic. Therefore, in silico studies have become an excellent tool for identifying possible ligands that could lead to the development of safer medicines or vaccines. Various phytoconstituents from plants and herbs with antiviral properties are studied further to obtain inhibitors of SARS-CoV-2. In silico screening of various molecular databases like PubChem, ZINC, Asinex Biol-Design Library, and so on has been performed extensively for finding effective ligands against targets. Herein, in silico studies carried out by various researchers are summarized so that one can easily find the best molecule for further in vitro and in vivo studies.

Exploring Toxins for Hunting SARS-CoV-2 Main Protease Inhibitors: Molecular Docking, Molecular Dynamics, Pharmacokinetic Properties, and Reactome Study.

The main protease (Mpro) is a potential druggable target in SARS-CoV-2 replication. Herein, an in silico study was conducted to mine for Mpro inhibitors from toxin sources. A toxin and toxin-target database (T3DB) was virtually screened for inhibitor activity towards the Mpro enzyme utilizing molecular docking calculations. Promising toxins were subsequently characterized using a combination of molecular dynamics (MD) simulations and molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations. According to the MM-GBSA binding energies over 200 ns MD simulations, three toxins-namely philanthotoxin (T3D2489), azaspiracid (T3D2672), and taziprinone (T3D2378)-demonstrated higher binding affinities against SARS-CoV-2 Mpro than the co-crystalized inhibitor XF7 with MM-GBSA binding energies of -58.9, -55.9, -50.1, and -43.7 kcal/mol, respectively. The molecular network analyses showed that philanthotoxin provides a ligand lead using the STRING database, which includes the biochemical top 20 signaling genes CTSB, CTSL, and CTSK. Ultimately, pathway enrichment analysis (PEA) and Reactome mining results revealed that philanthotoxin could prevent severe lung injury in COVID-19 patients through the remodeling of interleukins (IL-4 and IL-13) and the matrix metalloproteinases (MMPs). These findings have identified that philanthotoxin-a venom of the Egyptian solitary wasp-holds promise as a potential Mpro inhibitor and warrants further in vitro/in vivo validation.

Anticoronavirus Activity of Water-Soluble Pristine C60 Fullerenes: In Vitro and In Silico Screenings.

INTRODUCTION: The emergence of a new member of the Coronaviridae family, which caused the 2020 pandemic, requires detailed research on the evolution of coronaviruses, their structure and properties, and interaction with cells. Modern nanobiotechnologies can address the many clinical challenges posed by the COVID-19 pandemic. In particular, they offer new therapeutic approaches using biocompatible nanostructures with "specific" antiviral activity. Therefore, the nanosized spherical-like molecule (0.72 nm in diameter) composed of 60 carbon atoms, C60 fullerene, is of interest in terms of fighting coronaviruses due to its high biological activity. In here, we aim to evaluate the effectiveness of anticoronavirus action of water-soluble pristine C60 fullerene in the model and in vitro systems. As a model, apathogenic for human coronavirus, we used transmissible gastroenteritis virus of swine (TGEV), which we adapted to the BHK-21 cell culture (kidney cells of a newborn Syrian hamster). METHODS: The shape and size of the particles present in C60 fullerene aqueous colloidal solution (C60FAS) of given concentration, as well as C60FAS stability (value of zeta potential) were studied using microscopic (STM, scanning tunneling microscopy, and AFM, atomic force microscopy) and spectroscopic (DLS, dynamic light scattering) methods. The cytopathic effect of TGEV was determined with the help of a Leica DM 750 microscope and the degree of monolayer changes in cells was assessed. The microscopy of the viral suspension was performed using a high resolution transmission electron microscope (HRTEM; JEM-1230, Japan). Finally, the search for and design of optimal possible complexes between C60 fullerene and target proteins in the structure of SARS-CoV-2 coronavirus, evaluation of their stability in the simulated cellular environment were performed using molecular dynamics and docking methods. RESULTS: It was found that the maximum allowable cytotoxic concentration of C60 fullerene is 37.5 ± 3.0 µg/ml. The investigated C60FAS reduces the titer of coronavirus infectious activity by the value of 2.00 ± 0.08 TCID50/ml. It was shown that C60 fullerene interacts directly with SARS-CoV-2 proteins, such as RdRp (RNA-dependent RNA polymerase) and 3CLpro (3-chymotrypsin-like protease), which is critical for the life cycle of the coronavirus and, thus, inhibits its functional activity. In both cases, C60 fullerene fills the binding pocket and gets stuck there through stacking and steric interactions. CONCLUSION: Pioneer in vitro study to identify the anticoronavirus activity of water-soluble pristine C60 fullerenes indicates that they are highly promising for further preclinical studies, since a significant inhibition of the infectious activity of swine coronavirus of transmissible gastroenteritis in BHK-21 cell culture was found. According to molecular modeling results, it was shown that C60 fullerene can create the stable complexes with 3CLpro and RdRp proteins of SARS-CoV-2 coronavirus and, thus, suppress its functional activity.

In silico approach to predict the SARS-CoV-2 derived candidate MiRNAs as a potential antiviral therapy

Background: The coronavirus disease 2019 (COVID-19) is a contagious disease originating from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Previous experimental studies indicated that during viral infections, viral miRNAs (vmiRNAs) played key roles in pathogen-host interaction, immune escape, host cell death, and tumorigenesis. MiRNAs are small, single-stranded RNAs that exist in viruses as well as in animals. Thus, these molecules can play a pivotal role in viral disease pathogenesis. Objective: Since no approved drugs or vaccines currently exist for SARS-CoV-2 and its pathogenic mechanism is unknown, the present study aimed to explore and propose vmiRNA platforms as potential antiviral therapeutic agents against SARS-CoV-2. The development of antiviral drugs to target vmiRNAs may result in the down-regulation of viral virulence genes expression and suppression of viral proliferation. Methods: In this study, to attain insight into the potential role of SARS-CoV-2-derived miRNAs in viral infections, a set of computational methods was used to scan the SARS-CoV-2 genome, eventually predicting 13 potential candidate vmiRNAs. Furthermore, the potential genes were predicted in the human hosts that were the target of these candidate vmiRNAs by applying the mirPath software. Results: This study proposed a theory indicating that the predicted vmiRNAs might have a plausible role in altering human target gene expression, mainly contributing to a viral infectious state, inflammation, and immune system escape. These vmiRNAs might have therapeutic trends as antiviral agents against COVID-19 infection. Conclusion: The findings offered a reference idea for a supplementary study on miRNA identification as a drug target and revealed the necessity to increase the understanding of SARS-CoV-2 genome structure for a better combat against the virus. © 2021 Bentham Science Publishers.

Strategies for drug repurposing against coronavirus targets.

Repurposing regulatory agency approved drugs and investigational compounds with known safety profiles can significantly fast track the drug development timeline over de novo drug discovery, with lower investment requirements and improved attrition rate. These advantages are vital in any epidemic or pandemic situation, where hospital beds are occupied by patients for whom there is no known treatment. Here we examine drug repurposing in the context of human coronaviruses, SARS-CoV, MERS-CoV, and, in particular, SARS-CoV-2, the virus currently causing a continued widespread pandemic with substantial impacts on public health and economy. The key druggable targets explored were those involved in viral entry, viral replication, and viral-induced ARDS, as well as viral proteases, with a focus on the strategy by which the drugs were repurposed.

Target-Based In Silico Screening for Phytoactive Compounds Targeting SARS-CoV-2.

Coronavirus disease 2019 (COVID-19), resulting from infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can cause severe and fatal pneumonia along with other life-threatening complications. The COVID-19 pandemic has taken a heavy toll on the healthcare system globally and has hit the economy hard in all affected countries. As a result, there is an unmet medical need for both the prevention and treatment of COVID-19 infection. Several herbal remedies have claimed to show promising clinical results, but the mechanisms of action are not clear. We set out to identify the anti-viral natural products of these herbal remedies that presumably inhibit the life cycle of SARS-CoV-2. Particularly we chose four key SARS-CoV-2 viral enzymes as targets: Papain-like protease, Main protease, RNA dependent RNA polymerase, and 2'-O-ribose methyltransferase, which were subjected to an unbiased in silico screening against a small molecule library of 33,765 compounds originating from herbs and medicinal plants. The small molecules were then ranked based on their free energy of fitting into the "druggable" pockets on the surface of each target protein. We have analyzed the best "fit" molecules and annotated them according to their plant sources and pharmacokinetic properties. Here we present a list of potential anti-viral ingredients of herbal remedies targeting SARS-CoV-2 and explore the potential mechanisms of action of these compounds as a framework for further development of chemoprophylaxis agents against COVID-19.