New findings on ligand series used as SARS-CoV-2 virus inhibitors within the frameworks of molecular docking, molecular quantum similarity and chemical reactivity indices (original) (raw)
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Heliyon, 2021
The Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became a pandemic, resulting in an exponentially increased mortality globally and scientists all over the world are struggling to find suitable solutions to combat it. Multiple repurposed drugs have already been in several clinical trials or recently completed. However, none of them shows any promising effect in combating COVID-19. Therefore, developing an effective drug is an unmet global need. RdRp (RNA dependent RNA polymerase) plays a pivotal role in viral replication. Therefore, it is considered as a prime target of drugs that may treat COVID-19. In this study, we have screened a library of compounds, containing approved RdRp inhibitor drugs that were or in use to treat other viruses (favipiravir, sofosbuvir, ribavirin, lopinavir, tenofovir, ritonavir, galidesivir and remdesivir) and their structural analogues, in order to identify potential inhibitors of SARS-CoV-2 RdRp. Extensive screening, molecular docking and molecular dynamics show that five structural analogues have notable inhibitory effects against RdRp of SARS-CoV-2. Importantly, comparative protein-antagonists interaction revealed that these compounds fit well in the pocket of RdRp. ADMET analysis of these compounds suggests their potency as drug candidates. Our identified compounds may serve as potential therapeutics for COVID-19.
Repurposing of RdRp Inhibitors against SARS-CoV-2 through Molecular Docking Tools
Coronaviruses
In the present hour, the COVID-19 pandemic needs no introduction. There is continuous and keen research in progress in order to discover or develop a suitable therapeutic candidate/vaccine against the fatal, severe acute respiratory syndrome causing coronavirus (SARS-CoV-2). Drug repurposing is an approach of utilizing the therapeutic potentials of previously approved drugs against some new targets or pharmacological responses. In the presented work, we have evaluated the RNA dependent RNA polymerase (RdRp) inhibitory potentials of FDA approved anti-viral drugs remdesivir, ribavirin, sofosbuvir and galidesivir through molecular docking. The studies were carried out using MOE 2019.0102 software against RdRp (PDB ID:7BTF, released on 8th April, 2020). All four drugs displayed good docking scores and significant binding interactions with the amino acids of the receptor. The docking protocol was validated by redocking of the ligands and the root mean square deviation (RMSD) value was fo...
2020
The pandemic prevalence of COVID-19 has become a very serious global health issue. Scientists all over the world have been heavily invested in the discovery of a drug to combat SARS-CoV-2. It has been found that RNA-dependent RNA Polymerase (RdRp) plays a crucial role in SARS-CoV-2 replication, and thus could be a potential drug target. Here, comprehensive computational approaches including drug repurposing and molecular docking were employed to predict an effective drug candidate targeting RdRp of SARS-CoV-2. This study revealed that Rifabutin, Rifapentine, Fidaxomicin, 7-methyl-guanosine-5'-triphosphate-5'-guanosine and Ivermectin have a potential inhibitory interaction with RdRp of SARS-CoV-2, and could be effective drugs for COVID-19. In addition, virtual screening of the compounds from ZINC database also allowed the prediction of two compounds (ZINC09128258 and ZINC 09883305) with pharmacophore features that interact effectively with RdRp of SARS-CoV-2; indicating their...
Journal of Translational Medicine
Background: The Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) outbreak originating in Wuhan, China, has raised global health concerns and the pandemic has now been reported on all inhabited continents. Hitherto, no antiviral drug is available to combat this viral outbreak. Methods: Keeping in mind the urgency of the situation, the current study was designed to devise new strategies for drug discovery and/or repositioning against SARS-CoV-2. In the current study, RNA-dependent RNA polymerase (RdRp), which regulates viral replication, is proposed as a potential therapeutic target to inhibit viral infection. Results: Evolutionary studies of whole-genome sequences of SARS-CoV-2 represent high similarity (> 90%) with other SARS viruses. Targeting the RdRp active sites, ASP760 and ASP761, by antiviral drugs could be a potential therapeutic option for inhibition of coronavirus RdRp, and thus viral replication. Target-based virtual screening and molecular docking results show that the antiviral Galidesivir and its structurally similar compounds have shown promise against SARS-CoV-2. Conclusions: The anti-polymerase drugs predicted here-CID123624208 and CID11687749-may be considered for in vitro and in vivo clinical trials.
Journal of Biomolecular Structure and Dynamics
SARS-CoV-2 virus outbreak poses a major threat to humans worldwide due to its highly contagious nature. In this study, molecular docking, molecular dynamics, and structure-activity relationship are employed to assess the binding affinity and interaction of 76 prescription drugs against RNA dependent RNA polymerase (RdRp) and Main Protease (Mpro) of SARS-CoV-2. The RNA-dependent RNA polymerase is a vital enzyme of coronavirus replication/transcription complex whereas the main protease acts on the proteolysis of replicase polyproteins. Among 76 prescription antiviral drugs, four drugs (Raltegravir, Simeprevir, Cobicistat, and Daclatasvir) that are previously used for human immunodeficiency virus (HIV), hepatitis C virus (HCV), Ebola, and Marburg virus show higher binding energy and strong interaction with active sites of the receptor proteins. To explore the dynamic nature of the interaction, 100 ns molecular dynamics (MD) simulation is performed on the selected protein-drug complexes and apo-protein. Binding free energy of the selected drugs is performed by MM/PBSA. Besides docking and dynamics, partial least square (PLS) regression method is applied for the quantitative structure activity relationship to generate and predict the binding energy for drugs. PLS regression satisfactorily predicts the binding energy of the effective antiviral drugs compared to binding energy achieved from molecular docking with a precision of 85%. This study highly recommends researchers to screen these potential drugs in vitro and in vivo against SARS-CoV-2 for further validation of utility.
International journal of Advanced Biological and Biomedical Research, 2021
Background: SARS-CoV-2 is a novel coronavirus discovered in December 2019 and is responsible for pandemic disease COVID-19. In the absence of any available vaccines or drugs to combat the virus, it has caused enormous damage. Methods: An in-silico docking approach was applied to determine potential inhibitors of SARS-CoV-2 RNA-MTase by screening against a ligand library of FDA approved antiviral compounds. Results: Ten compounds including Daclatasvir, Pibrentasvir, Tenofovir, Velpatasvir, Grazoprevir, Ledipasvir, Elbasvir, Delavirdine, Nilutamide, and Ribavirin triphosphate showed a strong binding affinity with RNA-MTase of which Daclatasvir and Pibrentasvir exhibited the highest affinity. Moreover, Daclatasvir, Grazoprevir, and Tenofovir, which have recently been reported to have a binding affinity with other SARS-CoV-2 proteins, showed good binding interactions with RNA-MTase, suggesting a role to act as dual inhibitors. Conclusion: The suggested antiviral compounds can tightly b...
Health Science Monitor
The severe acute respiratory syndrome coronavirus 2 (known as COVID-19), initially appeared in the Wuhan city of China in December 2019, has become a current medical issue around the world. Due to its highly contagious nature, COVID-19 has spread widely to all countries. As no effective treatment or vaccine is developed for this infectious disease, preventive measures are the only mandatory strategy to stop its human-to-human transmission. In the present spread of COVID-19, the discovery of antiviral drugs is crucially important as the development of these drugs often takes time. However, no specific drug has yet been approved for COVID-19. In this review, we focus on the available drug candidates used for the treatment of infections caused by COVID-19 to identify potential inhibitors through molecular docking.