Fig 2 - available via license: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
Content may be subject to copyright.
Representations of protein-ligand complexes from molecular docking. A) 3D diagram of binding conformation of Fidaxomicin with RdRp-nsp12 along with the Hbonds formed in the complex and B) 2D diagram of hydrophobic interactions between Fidaxomicin and RdRp-nsp12 in the docked complex.
Source publication
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 accel...
Context in source publication
Context 1
... like hydrogen bond (H-bond), hydrophobic contacts (Table 2). ARG569, LYS577, ALA685, GLY590, and LYS593 were involved in H-bond formation, while the residues such as ASN497, LYS500, GLN573, LEU576, ILE589, THR591, SER592, LYS593, TRP598, MET601, SER682, ASP684, ALA685, ALA688, TYR689, LEU758, SER759, and GLN815 formed hydrophobic bonds (Fig. ...
Similar publications
Coronavirus disease 2019 (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently spreading rapidly around the world. Since SARS-CoV-2 seriously threatens human life and health as well as the development of the world economy, it is very urgent to identify effective drugs against this virus. However,...
Citations
... Several drugs have been repurposed based on their availability to inhibit RNAdependent-RNA polymerase (RdRp) and protease enzymes for the treatment of infections caused by RNA viruses. A number of FDA-approved RdRp inhibitors have shown effectiveness against a broad spectrum of RNA viruses such as hydroxychloroquine, remdesivir, ribavirin, favipiravir, galidesivir, kaletra, sofosbuvir, tenofovir, and ritonavir (Gangadharan et al. 2022). Moreover, Piplani et al. (2021) have predicted the potential repurposing of certain natural products, such as silibinin (an antioxidant and hepatoprotectant), digoxin (a cardiac drug of arrhythmia), and ivermectin (an antiparasitic), based on their binding affinity to RdRp. ...
Viral diseases pose significant challenges in human and veterinary medicine, as effective treatment options are limited. The development of antiviral drugs becomes increasingly challenging in the face of emerging and reemerging viral diseases. The genetic changes and rapid evolution of certain viruses further complicate the development of universal pathogen-specific drug therapies. Hence, there is a pressing need for research and development in the field of antiviral drugs. The novel approaches, such as computer-aided drug designing (CADD), have expedited the drug development process, notably reducing the preclinical phase. Phyto-medicines offer promising alternatives as antivirals, while organic polymers like extracellular polymeric substances (EPS) have demonstrated effectiveness in combating viruses. Additionally, exosomes have shown potential as antivirals and in antiviral delivery, particularly when loaded with drugs and specifically targeted against viral diseases. The repurposing of drugs for antiviral therapeutics has garnered significant attention in both research institutions and pharmaceutical industries due to its numerous advantages. Combination antiviral therapies not only reduce toxicity but also address issues of drug resistance. Lastly, extensive clinical trials will be crucial for the successful repurposing of drugs as antiviral therapeutics.
... One of these, known as Nsp12 or RNA-dependent RNA polymerase (RdRp), catalyzes the synthesis of viral RNA and plays a central role in the replication and transcription cycle of SARS-CoV-2 with Nsp7 and Nsp8 as co-factors [31,32]. Therefore, Nsp12 is considered a primary target for antiviral agents, with the potential for treating COVID-19 [33], and possibly other coronaviral diseases because it is a highly conserved motif. For example, sequence alignment results from the literature shows 96% common identity between SARS-CoV and SARS-CoV-2 [34]. ...
... Few studies also reported the screening of analogues of different scaffolds such as quinolines [47], cytidines [52] and andrographolides [53]. It's also common for repurposing efforts to propose drugs that are yet to be tested in vitro [27,33,[45][46][47][54][55][56][57][58][59][60]. ...
The novel coronavirus disease (COVID-19) pandemic has resulted in over 720 million confirmed cases and 7 million deaths worldwide, with insufficient treatment options. Innumerable efforts are being made around the world for faster identification of therapeutic agents to treat the deadly disease. Postacute sequelae of SARS-CoV-2 infection or COVID-19 (PASC), also called Long COVID, is still being understood and lacks treatment options as well. A growing list of drugs are being suggested by various in silico, in vitro and ex vivo models, however currently only two treatment options are widely used: the RNA-dependent RNA polymerase (RdRp) inhibitor remdesivir, and the main protease inhibitor nirmatrelvir in combination with ritonavir. Computational drug development tools and in silico studies involving molecular docking, molecular dynamics, entropy calculations and pharmacokinetics can be useful to identify new targets to treat COVID-19 and PASC, as shown in this work and our recent paper that identified alendronate as a promising candidate. We have now investigated all bisphosphonates which can bind competitively to nidovirus RdRp-associated nucleotidyl (NiRAN) transferase domain, and systematically down selected seven candidates (CHEMBL608526, CHEMBL196676, CHEMBL164344, CHEMBL4291724, CHEMBL4569308, CHEMBL387132, CHEMBL98211), two of which closely resemble the approved drugs minodronate and zoledronate. This work and our recent paper together provide an in silico mechanistic explanation for alendronate and zoledronate users having dramatically reduced odds of SARS-CoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations, and indicate that similar observational studies with minodronate could be valuable.
... One of these, known as Nsp12 or RNA-dependent RNA polymerase (RdRp), catalyzes the synthesis of viral RNA and plays a central role in the replication and transcription cycle of SARS-CoV-2 with Nsp7 and Nsp8 as co-factors [8,9]. Therefore, Nsp12 is considered a primary target for antiviral agents, with the potential for treating COVID-19 [10], and possibly other coronaviral diseases because it is a highly conserved motif. For example, sequence alignment results from the literature shows 96% common identity between SARS-CoV and SARS-CoV-2 [11]. ...
... Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 28 December 2023 doi:10.20944/preprints202311.1727.v210 ...
The novel coronavirus disease (COVID-19) pandemic has resulted in over 720 million confirmed cases and 7 million deaths worldwide, with insufficient treatment options. Innumerable efforts are being made around the world for faster identification of therapeutic agents to treat the deadly disease. Postacute sequelae of SARS-CoV-2 infection or COVID-19 (PASC), also called Long COVID, is still being understood and lacks treatment options as well. A growing list of drugs are being suggested by various in silico, in vitro and ex vivo models, however currently only two treatment options are widely used: the RNA-dependent RNA polymerase (RdRp) inhibitor remdesivir, and the main protease inhibitor nirmatrelvir in combination with ritonavir. Computational drug development tools and in silico studies involving molecular docking, molecular dynamics, entropy calculations and pharmacokinetics can be useful to identify new targets to treat COVID-19 and PASC, as shown in this paper. We have investigated bisphosphonates which can bind competitively to nidovirus RdRp-associated nucleotidyl (NiRAN) transferase domain, and systematically down selected seven candidates for further evaluation (CHEMBL608526, CHEMBL196676, CHEMBL164344, CHEMBL4291724, CHEMBL4569308, CHEMBL387132, CHEMBL98211). Interestingly, one of these (CHEMBL608526) very closely resembles the approved drug minodronate, and another (CHEMBL98211) resembles the approved drug zoledronate.
... Remdesivir, a nucleotide analog prodrug, has been shown to have broad-spectrum antiviral activity against SARS-CoV-2 [81][82][83]. In silico studies have demonstrated that Remdesivir can inhibit the RNA polymerase of SARS-CoV-2, thereby preventing viral replication [81,84]. Furthermore, Favipiravir, another nucleotide analog, has also shown promising results in in silico studies. ...
The COVID-19 pandemic has spurred intense research efforts to identify effective treatments for SARS-CoV-2. In silico studies have emerged as a powerful tool in the drug discovery process, particularly in the search for drug candidates that interact with various SARS-CoV-2 receptors. These studies involve the use of computer simulations and computational algorithms to predict the potential interaction of drug candidates with target receptors. The primary receptors targeted by drug candidates include the RNA polymerase, main protease, spike protein, ACE2 receptor, and transmembrane protease serine 2 (TMPRSS2). In silico studies have identified several promising drug candidates, including Remdesivir, Favipiravir, Ribavirin, Ivermectin, Lopinavir/Ritonavir, and Camostat Mesylate, among others. The use of in silico studies offers several advantages, including the ability to screen a large number of drug candidates in a relatively short amount of time, thereby reducing the time and cost involved in traditional drug discovery methods. Additionally, in silico studies allow for the prediction of the binding affinity of the drug candidates to target receptors, providing insight into their potential efficacy. This study is aimed at assessing the useful contributions of the application of computational instruments in the discovery of receptors targeted in SARS-CoV-2. It further highlights some identified advantages and limitations of these studies, thereby revealing some complementary experimental validation to ensure the efficacy and safety of identified drug candidates.
... However, a limited number of NNI were proposed as RdRp inhibitors. Rifabutin, Rifapentine, Fidaxomicin, 7GMT, and Ivermectin are a few of the NNI of RdRp, repurposed during the pandemic [19]. Based on this information, we understand that there is a need for targeted RdRp NNI inhibitors. ...
Background
The SARS-CoV2 was responsible for the pandemic situation across the world. SARS-CoV2 is an RNA virus, and its replication depends on RNA Dependent RNA Polymerase (RdRp). Hence, blocking of RdRP would be an alternative strategy to inhibit the virus multiplication without affecting the host physiology.
Objective
The current study investigated the inhibitory effect of bioactive compound F3 isolated from P. citrinum CGJ-C2 and its in-silico derivates against RdRp of COVID using computational methods.
Methods
Compound F3 and its derivatives were generated computationally, and the crystal structure of RdRp was processed prior to docking. The RdRp and the bioactive compounds were docked using Glide with three levels of precisions. Post-docking MMGBSA analysis and Molecular Dynamic simulations were carried out to study the stability of the docking interactions.
Results
Based on the Glide XP score and MMGBSA analysis of fifteen ligands, three leads were selected, compound F3 (-8.655 Kcal/mol), D-1(-8.295 Kcal/mol), and D-14(-8.262 Kcal/mol). These leads (Compound F3, D-1, and D-14) were further evaluated using molecular dynamics (MD) simulation. MD simulations studies showed the stable bonding interaction between LYS500 and ARG569 residues of RdRp with the three lead molecules.
Conclusion
Our study highlighted the potential of compounds in terms of binding, interaction stability, and structural integrity. Therefore, these leads can be chosen for further studies in in vitro and in vivo to develop a novel anti-SARS-CoV2 agent with minimal side effects.
... Molecular docking, molecular dynamics, solvent screening, and prediction of drug properties were also used to investigate compounds from the medicinal plant Myristica fragans on the protease target Mpro and the spike protein binding of SARS-CoV-2 with the cellular receptor ACE2 [19]. In the reuse of antiviral drugs against the RNAdependent RNA polymerase of SARS-CoV-2 by a computational approach, it used molecular docking and molecular dynamics to identify possible therapies for the treatment of the disease where several drugs were evaluated, identifying fidaxomicin as the best result [20]. ...
Context:
Heparin, one of the drugs reused in studies with antiviral activity, was chosen to investigate a possible blockade of the SARS-CoV-2 spike protein for viral entry through computational simulations and experimental analysis. Heparin was associated to graphene oxide to increase in the binding affinity in biological system. First, the electronic and chemical interaction between the molecules was analyzed through ab initio simulations. Later, we evaluate the biological compatibility of the nanosystems, in the target of the spike protein, through molecular docking. The results show that graphene oxide interacts with the heparin with an increase in the affinity energy with the spike protein, indicating a possible increment in the antiviral activity. Experimental analysis of synthesis and morphology of the nanostructures were carried out, indicating heparin absorption by graphene oxide, confirming the results of the first principle simulations. Experimental tests were conducted on the structure and surface of the nanomaterial, confirming the heparin aggregation on the synthesis with a size between the GO layers of 7.44 Å, indicating a C-O type bond, and exhibiting a hydrophilic surface characteristic (36.2°).
Methods:
Computational simulations of the ab initio with SIESTA code, LDA approximations, and an energy shift of 0.05 eV. Molecular docking simulations were performed in the AutoDock Vina software integrated with the AMDock Tools Software using the AMBER force field. GO, GO@2.5Heparin, and GO@5Heparin were synthesized by Hummers and impregnation methods, respectively, and characterized by X-ray diffraction and surface contact angle.
... It shows a binding affinity of −8.39 kcal/mol by forming an attractive charge interaction with ARG555, unfavourable attraction with Mg 2+ 1004, hydrophobic interaction with Mg 2+ 1005 and pi-pi stacked interaction with uracil (U20). Moreover, molnupiravir triphosphate also interacts with RdRp of the Delta AY.4 subvariant of SARS-CoV-2 through various types of interaction with crucial amino acid residues (CYS622, TYR622, LYS62, TRP617, ASP761 and U20) with a binding energy of −10.28 kcal/mol [121] (Fig. 13). Molnupiravir was investigated for mutagenicity in two rodent models in vivo. ...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic since 2019, spreading rapidly and posing a significant threat to human health and life. With over 6 billion confirmed cases of the virus, the need for effective therapeutic drugs has become more urgent than ever before. RNA-dependent RNA polymerase (RdRp) is crucial in viral replication and transcription, catalysing viral RNA synthesis and serving as a promising therapeutic target for developing antiviral drugs. In this article, we explore the inhibition of RdRp as a potential treatment for viral diseases, analysing the structural information of RdRp in virus proliferation and summarizing the reported inhibitors’ pharmacophore features and structure–activity relationship profiles. We hope that the information provided by this review will aid in structure-based drug design and aid in the global fight against SARS-CoV-2 infection.
Graphical Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third coronavirus to cause a global pandemic of significant human illnesses in the past two decades, following MERS and SARS (SARS). On January 30, 2020, WHO declared COVID-19 a global public health emergency. Governments enforced physical distance, hand hygiene, and personal safety equipment considering the virus’s ferocity and transmissibility. Vaccination and WHO-approved emergency antiviral medications were used to prevent and manage the COVID-19 pandemic. Some of the SARS-CoV-2 variants developed in a later phase were classified as variants of concern (VOC) by WHO because of their high virulence, increased mortality and morbidity, rendering repurposed treatments and vaccines ineffectual. Traditional herbal medications were explored widely in treating SARS-CoV-2 in India, China, Africa, and other nations. The epidemic expanded the global use of secondary metabolites-based herbal treatments. By strengthening human immunity, medicinal herbs indirectly affect the virus. Several in silico, in vitro, in vivo, and clinical investigations showed the potential of herbal medication to treat and prevent COVID-19. Earlier under similar situations, herbal medicines or plant secondary metabolites (PSM) with therapeutic potential have been used to treat several chronic diseases due to their structural diversity and abundance. Several investigations evidenced that target-based phyto-molecule or herbal formulations are appropriate alternative treatments for reducing virus entrance and replication and enhancing host immunity. In this chapter, a methodical review of reported traditional herbal medicines for COVID-19 revealed a wide variety of medicinal formulations and prospective plants that may help manage and treat SARS-CoV-2. This chapter examines herbal formulations’ active principles and mechanisms for suppressing SARS-CoV-2 infection at various levels.KeywordsSpike proteinAngiotensin-converting enzyme-2Herbal formulationsImmunityAYUSHComputational study
