RNA-dependent RNA Polymerase Inhibitors Research Articles

Real-World Experience with Favipiravir for the Treatment of Mild-to-Moderate COVID-19 in India.

BackgroundFavipiravir, an RNA-dependent RNA polymerase inhibitor (RdRp), is a broad-spectrum oral antiviral agent approved in India under emergency use authorization, for the treatment of mild-to-moderate coronavirus disease (COVID-19). The present study was planned to evaluate the effectiveness and safety of favipiravir in real-world clinical practice.Materials and MethodsThis was a multicentric, retrospective, single-arm study conducted across four centres in India, after obtaining permission from the independent ethics committee. Medical records were analysed to evaluate effectiveness and safety of patients who were prescribed favipiravir.ResultsThe medical records of a total of 360 patients met the inclusion criteria, with 358 of them available for the final analysis. Males made up 58.46% of the study population. The average age of enrolled patients was 51.80 ± 16.45 years. The most common symptoms were fever, cough, and myalgia-fatigue. The median time to clinical cure and fever relief was five and four days, respectively. The average length of stay in the hospital was six days. In total, 8% of the patients experienced adverse events. Hepatic enzyme elevation, diarrhoea, decreased appetite, headache, fatigue, and giddiness were the common symptoms.ConclusionIn our real-world study, favipiravir was found to have a clinical cure rate of more than 90% in mild-to-moderate COVID-19 patients. This supports the use of favipiravir in the treatment of COVID-19. Favipiravir was well tolerated, with only minimal side effects, which were transient in nature.

Immune-related therapeutics: an update on antiviral drugs and vaccines to tackle the COVID-19 pandemic.

The coronavirus disease 2019 (COVID-19) pandemic rapidly spread globally. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, is a positive-sense single-stranded RNA virus with a reported fatality rate ranging from 1% to 7%, and people with immune-compromised conditions, children, and older adults are particularly vulnerable. Respiratory failure and cytokine storm-induced multiple organ failure are the major causes of death. This article highlights the innate and adaptive immune mechanisms of host cells activated in response to SARS-CoV-2 infection and possible therapeutic approaches against COVID-19. Some potential drugs proven to be effective for other viral diseases are under clinical trials now for use against COVID-19. Examples include inhibitors of RNA-dependent RNA polymerase (remdesivir, favipiravir, ribavirin), viral protein synthesis (ivermectin, lopinavir/ritonavir), and fusion of the viral membrane with host cells (chloroquine, hydroxychloroquine, nitazoxanide, and umifenovir). This article also presents the intellectual groundwork for the ongoing development of vaccines in preclinical and clinical trials, explaining potential candidates (live attenuated-whole virus vaccines, inactivated vaccines, subunit vaccines, DNA-based vaccines, protein-based vaccines, nanoparticle-based vaccines, virus-like particles and mRNA-based vaccines). Designing and developing an effective vaccine (both prophylactic and therapeutic) would be a long-term solution and the most effective way to eliminate the COVID-19 pandemic.

A retrospective, observational study: early versus late favipiravir in COVID-19 pneumonia

Aim: Positive results have been reported regarding the early use of favipiravir,a RNA-dependent RNA polymerase inhibitor,in the COVID-19 pandemic. In our study, we aimed to understand the potential role of favipiravir in controlling COVID-19 pneumonia and sepsis by comparing the early use of favipiravir with the late using.
 Material and Method: Treatments are carried out in line with the guidelines constantly updated by the Ministry of Health in Turkey. Following the guide published on April 14,2020,we examined 18 patients who received favipiravir as the last treatment option in the late period and 17 patients who received favipiravir in the early period in two different groups.We recorded the demographic characteristics,comorbidities,APACHE-II scores,consecutive SOFA scores and mortality status of the patients in both groups.
 Results: The difference between groups in terms of gender and age was not statistically significant.The difference between groups in terms of APACHE-II score was statistically significant.(p=0.018)The late group also had higher APACHE-II scores.The difference between groups in terms of exitus was not statistically significant but lower in the group using favipiravir early.
 Conclusion: In studies with a limited number of patients, favipiravir has been shown to have a significant advantage over lopinavir/ritonavir in viral clearance as well as a significant reduction in viral load when used in the early period.Similarly,in our study,patients who used favipiravir in the late period came to us more seriously and the mortality rate was higher. We think that favipiravir had a significant effect even in studies with a small number of patients, and larger studies are needed in this area.

Structure-based screening of natural product libraries in search of potential antiviral drug-leads as first-line treatment to COVID-19 infection

The study focuses on identifying and screening natural products (NPs) based on their structural similarities with chemical drugs followed by their possible use in first-line treatment to COVID-19 infection. In the present study, the in-house natural product libraries, consisting of 26,311 structures, were screened against potential targets of SARS-CoV-2 based on their structural similarities with the prescribed chemical drugs. The comparison was based on molecular properties, 2 and 3-dimensional structural similarities, activity cliffs, and core fragments of NPs with chemical drugs. The screened NPs were evaluated for their therapeutic effects based on their predicted in-silico pharmacokinetic and pharmacodynamics properties, binding interactions with the appropriate targets, and structural stability of the bound complex using molecular dynamics simulations. The study yielded NPs with significant structural similarities to synthetic drugs currently used to treat COVID-19 infections. The study proposes the probable biological action of the selected NPs as Anti-retroviral protease inhibitors, RNA-dependent RNA polymerase inhibitors, and viral entry inhibitors.

The development of broad-spectrum antiviral medical countermeasures to treat viral hemorrhagic fevers caused by natural or weaponized virus infections.

The Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense (JPEO-CBRND) began development of a broad-spectrum antiviral countermeasure against deliberate use of high-consequence viral hemorrhagic fevers (VHFs) in 2016. The effort featured comprehensive preclinical research, including laboratory testing and rapid advancement of lead molecules into nonhuman primate (NHP) models of Ebola virus disease (EVD). Remdesivir (GS-5734, Veklury, Gilead Sciences) was the first small molecule therapeutic to successfully emerge from this effort. Remdesivir is an inhibitor of RNA-dependent RNA polymerase, a viral enzyme that is essential for viral replication. Its robust potency and broad-spectrum antiviral activity against certain RNA viruses including Ebola virus and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) led to its clinical evaluation in randomized, controlled trials (RCTs) in human patients during the 2018 EVD outbreak in the Democratic Republic of the Congo (DRC) and the ongoing Coronavirus Disease 2019 (COVID-19) pandemic today. Remdesivir was recently approved by the US Food and Drug Administration (FDA) for the treatment of COVID-19 requiring hospitalization. Substantial gaps remain in improving the outcomes of acute viral infections for patients afflicted with both EVD and COVID-19, including how to increase therapeutic breadth and strategies for the prevention and treatment of severe disease. Combination therapy that joins therapeutics with complimentary mechanisms of action appear promising, both preclinically and in RCTs. Importantly, significant programmatic challenges endure pertaining to a clear drug and biological product development pathway for therapeutics targeting biodefense and emerging pathogens when human efficacy studies are not ethical or feasible. For example, remdesivir’s clinical development was facilitated by outbreaks of Ebola and SARS-CoV-2; as such, the development pathway employed for remdesivir is likely to be the exception rather than the rule.The current regulatory licensure pathway for therapeutics targeting rare, weaponizable VHF agents is likely to require use of FDA’s established Animal Rule (21 CFR 314.600–650 for drugs; 21 CFR 601.90–95 for biologics). The FDA may grant marketing approval based on adequate and well-controlled animal efficacy studies when the results of those studies establish that the drug is safe and likely to produce clinical benefit in humans. In practical terms, this is anticipated to include a series of rigorous, well-documented, animal challenge studies, to include aerosol challenge, combined with human safety data. While small clinical studies against naturally occurring, high-consequence pathogens are typically performed where possible, approval for the therapeutics currently under development against biodefense pathogens will likely require the Animal Rule pathway utilizing studies in NHPs. We review the development of remdesivir as illustrative of the effort that will be needed to field future therapeutics against highly lethal, infectious agents.

Multi-Phase In Silico Discovery of Potential SARS-CoV-2 RNA-Dependent RNA Polymerase Inhibitors among 3009 Clinical and FDA-Approved Related Drugs

Proceeding our prior studies of SARS-CoV-2, the inhibitory potential against SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) has been investigated for a collection of 3009 clinical and FDA-approved drugs. A multi-phase in silico approach has been employed in this study. Initially, a molecular fingerprint experiment of Remdesivir (RTP), the co-crystallized ligand of the examined protein, revealed the most similar 150 compounds. Among them, 30 compounds were selected after a structure similarity experiment. Subsequently, the most similar 30 compounds were docked against SARS-CoV-2 RNA-dependent RNA polymerase (PDB ID: 7BV2). Aloin 359, Baicalin 456, Cefadroxil 1273, Sophoricoside 1459, Hyperoside 2109, and Vitexin 2286 exhibited the most precise binding modes, as well as the best binding energies. To confirm the obtained results, MD simulations experiments have been conducted for Hyperoside 2109, the natural flavonoid glycoside that exhibited the best docking scores, against RdRp (PDB ID: 7BV2) for 100 ns. The achieved results authenticated the correct binding of 2109, showing low energy and optimum dynamics. Our team presents these outcomes for scientists all over the world to advance in vitro and in vivo examinations against COVID-19 for the promising compounds.

Screening of potential inhibitors of COVID-19 with repurposing approach via molecular docking.

SARS-CoV-2 (COVID-19) is the causative organism for a pandemic disease with a high rate of infectivity and mortality. In this study, we aimed to assess the affinity between several available small molecule and proteins, including Abl kinase inhibitors, Janus kinase inhibitor, dipeptidyl peptidase 4 inhibitors, RNA-dependent RNA polymerase inhibitors, and Papain-like protease inhibitors, using binding simulation, to test whether they may be effective in inhibiting COVID-19 infection through several mechanisms. The efficiency of inhibitors was evaluated based on docking scores using AutoDock Vina software. Strong ligand–protein interactions were predicted among some of these drugs, that included: Imatinib, Remdesivir, and Telaprevir, and this may render these compounds promising candidates. Some candidate drugs might be efficient in disease control as potential inhibitors or lead compounds against the SARS-CoV-2. It is also worth highlighting the powerful immunomodulatory role of other drugs, such as Abivertinib that inhibits pro-inflammatory cytokine production associated with cytokine release syndrome (CRS) and the progression of COVID-19 infection. The potential role of other Abl kinase inhibitors, including Imatinib in reducing SARS-CoV and MERS-CoV viral titers, immune regulatory function and the development of acute respiratory distress syndrome (ARDS), indicate that this drug may be useful for COVID-19, as the SARS-CoV-2 genome is similar to SARS-CoV.

New Analogues of Uridine as Possible Anti-Viral Agents Specific to SARS-CoV-2

The development of specific drugs against SARS-CoV-2 infection is a major challenge facing global science and healthcare. Despite numerous attempts, there are still no truly effective drugs. Currently, the main approach in the creation of drugs against COVID-19 is repurposing, i.e., re-profiling existing drugs approved for medical use, for example, the use of a drug for the treatment of Ebola-Remdesivir, and the use of a drug for the treatment of influenza-Favipiravir. However, it is already obvious that these drugs are not specific enough nor effective enough. Another promising approach is the creation of new molecules, but it should be noted immediately that implementation requires much more time and costs. However, the search for new SARS-CoV-2 specific antiviral agents continues. The aim of our work was the creation of new 5-substituted uridine derivatives as potential inhibitors of coronavirus RNA-dependent RNA polymerase. The substances were obtained in high yields by the Suzuki-Miyaura reaction and characterized using modern physicochemical methods. However, testing of their antiviral activity against SARS-CoV-2 did not reveal a significant inhibitory effect.

Very low levels of remdesivir resistance in SARS-COV-2 genomes after 18 months of massive usage during the COVID19 pandemic: A GISAID exploratory analysis

Massive usage of antiviral compounds during a pandemic creates an ideal ground for emergence of resistant strains. Remdesivir, a broad-spectrum inhibitor of the viral RNA-dependent RNA polymerase (RdRp), was extensively prescribed under emergency use authorization during the first 18 months of the COVID19 pandemic, before randomized controlled trials showed poor efficacy in hospitalized patients. RdRp mutations conferring resistance to remdesivir are well known from in vitro studies, and the huge SARS-CoV-2 sequencing effort during the ongoing COVID19 pandemic represents an unprecedented opportunity to assess emergence and fitness of antiviral resistance in vivo. We mined the GISAID database to extrapolate the frequency of remdesivir escape mutations. Our analysis reveals very low levels of remdesivir resistance worldwide despite massive usage.

Should remdesivir be recommended in France in the early stage of COVID-19

COVID-19 due to SARS-CoV-2, has become a raging pandemic. Remdesivir, an RNA-dependent RNA polymerase (RdRP) inhibitor, was the first antiviral drug to be approved for SARS-CoV-2 in the United States (Beigel et al., 2020) and Europe (European Medicine Agency, 2020) and affects the hospital length of stay but not mortality (Goldman et al., 2020). The Solidarity and Discovery trials did not find a clinical benefit from the use of remdesivir in COVID-19 treatment (Ader et al., 2021, Consortium et al., 2021).

Eight Years of Research Advances in Bourbon Virus, a Tick-borne Thogotovirus of the Orthomyxovirus Family

Bourbon virus (BRBV) was first isolated from a blood sample collected from a male patient living in Bourbon County, Kansas, during the spring of 2014. The patient later died because of complications associated with multiorgan failure. Several deaths due to BRBV infection have since been reported in the United States, and misdiagnosed cases are often undercounted. BRBV is a member of the genus Thogotovirus of the Orthomyxoviridae family, and is transmitted through the Lone Star tick, Amblyomma americanum, in North America. Currently, no specific antiviral agents or vaccines are available to treat or prevent BRBV infection. Several small-molecular compounds have been identified to effectively inhibit BRBV infection of in vitro cell cultures at the single- or sub-micromolar level. Favipiravir, an RNA-dependent RNA polymerase inhibitor, has been found to prevent death in type I interferon receptor knockout mice with BRBV infection.

Synergistic Effects of Multiple Factors Involved in COVID-19-dependent Muscle Loss.

The COVID-19 pandemic caused by the novel SARS-CoV-2 coronavirus is an ongoing pandemic causing severe health crisis worldwide. Recovered COVID-19 patients go through several long-term side effects such as fatigue, headaches, dizziness, weight loss, and muscle loss among others. Our study sought to determine the molecular mechanisms behind muscle loss in COVID-19 patients. We hypothesized that multiple factors such as cytokine storm and therapeutic drugs (glucocorticoid and antiviral drugs) might be involved in muscle loss. Using the Gene Expression Omnibus database, we identified several studies that performed RNA sequencing on skeletal muscles with the treatment of cytokine, glucocorticoid, and antiviral drugs. Our study identified cytokines, such as IL-1b, and IL-6, associated with altered regulation of several genes involved in the myogenic processes, including Ttn, Cxxc5, Malat1, and Foxo1. We also observed that glucocorticoid altered the expression of Foxo1, Lcn2, Slc39a14, and Cdkn1a. Finally, we found out that the antiviral (RNA-dependent RNA polymerase inhibitor) drug regulates the expression of some of the muscle-related genes (Txnip, Ccnd1, Hdac9, and Fbxo32). Based on our findings, we hypothesize that the cytokine storm, glucocorticoids, and antiviral drugs might be synergistically involved in COVID-19-dependent muscle loss.

Predicting New Anti-Norovirus Inhibitor With the Help of Machine Learning Algorithms and Molecular Dynamics Simulation-Based Model.

Hepatitis C virus (HCV) inhibitors are essential in the treatment of human norovirus (HuNoV). This study aimed to map out HCV NS5B RNA-dependent RNA polymerase inhibitors that could potentially be responsible for the inhibitory activity of HuNoV RdRp. It is necessary to develop robust machine learning and in silico methods to predict HuNoV RdRp compounds. In this study, Naïve Bayesian and random forest models were built to categorize norovirus RdRp inhibitors from the non-inhibitors using their molecular descriptors and PubChem fingerprints. The best model observed had accuracy, specificity, and sensitivity values of 98.40%, 97.62%, and 97.62%, respectively. Meanwhile, an external test set was used to validate model performance before applicability to the screened HCV compounds database. As a result, 775 compounds were predicted as NoV RdRp inhibitors. The pharmacokinetics calculations were used to filter out the inhibitors that lack drug-likeness properties. Molecular docking and molecular dynamics simulation investigated the inhibitors’ binding modes and residues critical for the HuNoV RdRp receptor. The most active compound, CHEMBL167790, closely binds to the binding pocket of the RdRp enzyme and depicted stable binding with RMSD 0.8–3.2 Å, and the RMSF profile peak was between 1.0–4.0 Å, and the conformational fluctuations were at 450–460 residues. Moreover, the dynamic residue cross-correlation plot also showed the pairwise correlation between the binding residues 300–510 of the HuNoV RdRp receptor and CHEMBL167790. The principal component analysis depicted the enhanced movement of protein atoms. Moreover, additional residues such as Glu510 and Asn505 interacted with CHEMBL167790 via water bridge and established H-bond interactions after the simulation. http://zinc15.docking.org/substances/ZINC000013589565.

Molnupiravir-A Novel Oral Anti-SARS-CoV-2 Agent.

Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly resulted in a global pandemic with approximately 4 million deaths. Effective oral antiviral agents are urgently needed to treat coronavirus disease-2019 (COVID-19), block SARS-CoV-2 transmission, and prevent progression to severe illness. Molnupiravir (formerly EIDD-2801), a prodrug of beta-d-N4-hydroxycytidine (EIDD-1931) and an inhibitor of RNA-dependent RNA polymerase, possesses significant activity against SARS-CoV-2. Its prophylactic efficacy has been evidenced in a ferret model. Two phase-I trials (NCT04392219 and NCT04746183) have demonstrated that oral molnupiravir is safe and well-tolerated at therapeutic doses. After five-days of oral molnupiravir therapy, satisfactory efficacies, assessed by eliminating nasopharyngeal virus in patients with early and mild COVID-19, were disclosed in two phase-II trials (NCT04405739 and NCT 04405570). Two phase-II/III trials, NCT04575597 and NCT04575584, with estimated enrollments of 1850 and 304 cases, respectively, are ongoing. The NCT04575597 recently released that molnupiravir significantly reduced the risk of hospitalization or death in adults experiencing mild or moderate COVID-19. To benefit individual and public health, clinical applications of molnupiravir to promptly treat COVID-19 patients and prevent SARS-CoV-2 transmission may be expected.

Potential Novel Thioether-Amide or Guanidine-Linker Class of SARS-CoV-2 Virus RNA-Dependent RNA Polymerase Inhibitors Identified by High-Throughput Virtual Screening Coupled to Free-Energy Calculations.

SARS-CoV-2, or severe acute respiratory syndrome coronavirus 2, represents a new pathogen from the family of Coronaviridae that caused a global pandemic of COVID-19 disease. In the absence of effective antiviral drugs, research of novel therapeutic targets such as SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) becomes essential. This viral protein is without a human counterpart and thus represents a unique prospective drug target. However, in vitro biological evaluation testing on RdRp remains difficult and is not widely available. Therefore, we prepared a database of commercial small-molecule compounds and performed an in silico high-throughput virtual screening on the active site of the SARS-CoV-2 RdRp using ensemble docking. We identified a novel thioether-amide or guanidine-linker class of potential RdRp inhibitors and calculated favorable binding free energies of representative hits by molecular dynamics simulations coupled with Linear Interaction Energy calculations. This innovative procedure maximized the respective phase-space sampling and yielded non-covalent inhibitors representing small optimizable molecules that are synthetically readily accessible, commercially available as well as suitable for further biological evaluation and mode of action studies.

In silico identification of novel benzophenone–coumarin derivatives as SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibitors

In this study, we propose our novel benzophenone–coumarin derivatives (BCDs) as potent inhibitors of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 virus, one of the key targets that are involved in the viral genome replication. We aim to evaluate the in silico antiviral potential of BCDs against this protein target, which involves molecular docking simulations, druglikeliness and pharmacokinetic evaluations, PASS analysis, molecular dynamics simulations, and computing binding free energy. Out of all the BCDs screened through these parameters, BCD-8 was found to be the most efficient and potent inhibitor of SARS-CoV-2 RdRp. During molecular docking simulation, BCD-8 showed an extensive molecular interaction in comparison with that of the standard control used, remdesivir. The druglikeliness and pharmacokinetic analyses also proved the efficiency of BCD-8 as an effective drug without adverse effects. Further, pharmacological potential analysis through PASS depicted the antiviral property of BCD-8. With these findings, we performed molecular dynamics simulations, where BCD-8 edged out remdesivir with its exemplary stable interaction with SARS-CoV-2 RdRp. Furthermore, binding free energy of both BCD-8 and remdesivir was calculated, where BCD-8 showed a lower binding energy and standard deviations in comparison with that of remdesivir. Moreover, being a non-nucleoside analogue, BCD-8 can be used effectively against SARS-CoV-2, whereas nucleoside analogues like remdesivir may become non-functional or less functional due to exonuclease activity of nsp14 of the virus. Therefore, we propose BCD-8 as a SARS-CoV-2 RdRp inhibitor, showing higher predicted efficiency than remdesivir in all the in silico experiments conducted. Communicated by Ramaswamy H. Sarma

In Silico Structure-Based Design of Antiviral Peptides Targeting the Severe Fever with Thrombocytopenia Syndrome Virus Glycoprotein Gn.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus in Asia that causes severe disease. Despite its clinical importance, treatment options for SFTSV infection remains limited. The SFTSV glycoprotein Gn plays a major role in mediating virus entry into host cells and is therefore a potential antiviral target. In this study, we employed an in silico structure-based strategy to design novel cyclic antiviral peptides that target the SFTSV glycoprotein Gn. Among the cyclic peptides, HKU-P1 potently neutralizes the SFTSV virion. Combinatorial treatment with HKU-P1 and the broad-spectrum viral RNA-dependent RNA polymerase inhibitor favipiravir exhibited synergistic antiviral effects in vitro. The in silico peptide design platform in this study may facilitate the generation of novel antiviral peptides for other emerging viruses.

Indole Chloropyridinyl Ester-Derived SARS-CoV-2 3CLpro Inhibitors: Enzyme Inhibition, Antiviral Efficacy, Structure-Activity Relationship, and X-ray Structural Studies.

Here, we report the synthesis, structure–activity relationship studies, enzyme inhibition, antiviral activity, and X-ray crystallographic studies of 5-chloropyridinyl indole carboxylate derivatives as a potent class of SARS-CoV-2 chymotrypsin-like protease inhibitors. Compound 1 exhibited a SARS-CoV-2 3CLpro inhibitory IC50 value of 250 nM and an antiviral EC50 value of 2.8 μM in VeroE6 cells. Remdesivir, an RNA-dependent RNA polymerase inhibitor, showed an antiviral EC50 value of 1.2 μM in the same assay. Compound 1 showed comparable antiviral activity with remdesivir in immunocytochemistry assays. Compound 7d with an N-allyl derivative showed the most potent enzyme inhibitory IC50 value of 73 nM. To obtain molecular insight into the binding properties of these molecules, X-ray crystal structures of compounds 2, 7b, and 9d-bound to SARS-CoV 3CLpro were determined, and their binding properties were compared.

Assessing In Vitro Resistance Development in Enterovirus A71 in the Context of Combination Antiviral Treatment.

There are currently no antivirals available to treat infection with enterovirus A71 (EV-A71) or any other enterovirus. The extensively studied capsid binders rapidly select for drug-resistant variants. We here explore whether the combination of two direct-acting enterovirus inhibitors with a different mechanism of action may delay or prevent resistance development to the capsid binders. To that end, the in vitro dynamics of resistance development to the capsid binder pirodavir was studied either alone or in combination with a viral 2C-targeting compound (SMSK_0213), a viral 3C-protease inhibitor (rupintrivir) or a viral RNA-dependent RNA polymerase inhibitor (7DMA). We demonstrate that combining pirodavir with either rupintrivir or 7DMA delays the development of resistance to pirodavir and that no resistance to the protease or polymerase inhibitor develops. The combination of pirodavir with the 2C inhibitor results in a double-resistant virus population, where only the minority carries the resistant mutation.

Identification of SARS-CoV-2 RNA-dependent RNA polymerase inhibitors from the major phytochemicals of Nigella sativa: An in silico approach.

The coronavirus disease 2019 (COVID-19), which emerged in December 2019, continues to be a serious health concern worldwide. There is an urgent need to develop effective drugs and vaccines to control the spread of this disease. In the current study, the main phytochemical compounds of Nigella sativa were screened for their binding affinity for the active site of the RNA-dependent RNA polymerase (RdRp) enzyme of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The binding affinity was investigated using molecular docking methods, and the interaction of phytochemicals with the RdRp active site was analyzed and visualized using suitable software. Out of the nine phytochemicals of N. sativa screened in this study, a significant docking score was observed for four compounds, namely α-hederin, dithymoquinone, nigellicine, and nigellidine. Based on the findings of our study, we report that α-hederin, which was found to possess the lowest binding energy (–8.6 kcal/mol) and hence the best binding affinity, is the best inhibitor of RdRp of SARS-CoV-2, among all the compounds screened here. Our results prove that the top four potential phytochemical molecules of N. sativa, especially α-hederin, could be considered for ongoing drug development strategies against SARS-CoV-2. However, further in vitro and in vivo testing are required to confirm the findings of this study.