RdRp (RNA-dependent RNA polymerase): A key target providing anti-virals for the management of various viral diseases.
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ABSTRACT:
SUBMITTER: Pathania S
PROVIDER: S-EPMC8520695 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:RNA-dependent RNA polymerase (RdRp), also called nsp12, is considered a promising but challenging drug target for inhibiting replication and hence, the growth of various RNA-viruses. In this report, a computational study is performed to offer insights on the binding of Remdesivir and Galidesivir with SARS-CoV2 RdRp with natural substrate, ATP, as the control. It was observed that Remdesivir and Galidesivir exhibited similar binding energies for their best docked poses, -6.6 kcal/mole and -6.2 kcal/mole, respectively. ATP also displayed comparative and strong binding free energy of -6.3 kcal/mole in the catalytic site of RdRp. However, their binding locations within the active site are distinct. Further, the interaction of catalytic site residues (Asp760, Asp761, and Asp618) with Remdesivir and Galidesivir is comprehensively examined. Conformational changes of RdRp and bound molecules are demonstrated using 100 ns explicit solvent simulation of the protein-ligand complex. Simulation suggests that Galidesivir binds at the non-catalytic location and its binding strength is relatively weaker than ATP and Remdesivir. Remdesivir also binds at the catalytic site and showed high potency to inhibit the function of RdRp. Binding of co-factor units nsp7 and nsp8 with RdRp (nsp12) complexed with Remdesivir and Galidesivir was also examined. MMPBSA binding energy for all three complexes has been computed across the 100 ns simulation trajectory. Overall, this study suggests, Remdesivir has anti-RdRp activity via binding at a catalytic site. In contrast, Galidesivir may not have direct anti-RdRp activity but it can induce a conformational change in the RNA polymerase.
| S-EPMC7852292 | biostudies-literature
Project description:A recent outbreak of coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 has driven a global pandemic with catastrophic consequences. The rapid development of promising therapeutic strategies against COVID-19 is keenly anticipated. Family Coronaviridae comprises positive, single-stranded RNA viruses that use RNA-dependent RNA polymerase (RdRP) for viral replication and transcription. As the RdRP of viruses in this family and others plays a pivotal role in infection, it is a promising therapeutic target for developing antiviral agents against them. A critical genetic driver for many cancers is the catalytic subunit of telomerase: human telomerase reverse transcriptase (hTERT), identified initially as an RNA-dependent DNA polymerase. However, even though hTERT is a DNA polymerase, it has phylogenetic and structural similarities to viral RdRPs. Researchers worldwide, including the authors of this review, are engaged in developing therapeutic strategies targeting hTERT. We have published a series of papers reporting that hTERT has RdRP activity and that this RdRP activity in hTERT is essential for tumor formation. Here, we review the enzymatic function of RdRP in virus proliferation and tumor development, reminding us of how the study of the novel coronavirus has brought us to the unexpected intersection of cancer research and RNA virus research.
| S-EPMC7461281 | biostudies-literature
Project description:Circular RNAs (circRNAs) are recognized as a novel type of single-stranded endogenous noncoding RNA molecule with the characteristics of tissue specificity, sequence conservation and structural stability. Accumulating studies have shown that circRNAs play a unique biological role in different kinds of diseases. CircRNAs can affect tumor proliferation, migration, metastasis and other behaviors by modulating the expression of downstream genes. CircSMARCA5, an example of a circRNA, is dysregulated in various noninfectious diseases, such as tumors, osteoporosis, atherosclerosis and coronary heart disease. Furthermore, recent studies have demonstrated that circSMARCA5 is associated with the occurrence and development of a variety of tumors, including gastric cancer, glioblastoma, hepatocellular carcinoma, multiple myeloma, colorectal cancer, breast cancer and osteosarcoma. Mechanistically, circSMARCA5 primarily acts as a sponge of miRNAs to regulate the expression of downstream genes, and can serve as a potential biomarker for the diagnosis of malignant tumors. This review summarizes the biological roles of circSMARCA5 and its molecular mechanism of action in various diseases. Moreover, the meta-analysis of some publications showed that the expression of circSMARCA5 was significantly correlated with the prognosis of patients and tumor TNM stage, showing that circSMARCA5 has the potential to be a prognostic marker.
| S-EPMC9445203 | biostudies-literature
Project description:Several existing drugs have gained initial consideration due to their therapeutic characteristics against COVID-19 (Corona Virus Disease 2019). Hydroxychloroquine (HCQ) was proposed as possible therapy for shortening the duration of COVID-19, but soon after this, it was discarded. Similarly, known antiviral compounds were also proposed and investigated to treat COVID-19. We report a pharmacophore screening using essential chemical groups derived from HCQ and known antivirals to search a natural compound chemical space. Molecular docking of HCQ under physiological condition with spike protein, 3C-like protease (3CLpro), and RNA-dependent RNA polymerase (RdRp) of SARS-CoV2 showed - 8.52 kcal/mole binding score with RdRp, while the other two proteins showed relatively weaker binding affinity. Docked complex of RdRp-HCQ is further examined using 100 ns molecular dynamic simulation. Docking and simulation study confirmed active chemical moieties of HCQ, treated as 6-point pharmacophore to screen ZINC natural compound database. Pharmacophore screening resulted in the identification of potent hit molecule [(3S,3aR,6R,6aS)-3-(5-phenylsulfanyltetrazol-1-yl)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]N-naphthalen-ylcarbamate from natural compound library. Additionally, a set of antiviral compounds with similar chemical scaffolds are also used to design a separate ligand-based pharmacophore screening. Antiviral pharmacophore screening produced a potent hit 4-[(1,5-dimethyl-3-oxo-2-phenylpyrazol-4-yl)-(2-hydroxyphenyl)methyl]-1,5-dimethyl-2-phenylpyrazol-3-one containing essential moieties that showed affinity towards RdRp. Further, both these screened compounds are docked (- 8.69 and - 8.86 kcal/mol) and simulated with RdRp protein for 100 ns in explicit solvent medium. They bind at the active site of RdRp and form direct/indirect interaction with ASP618, ASP760, and ASP761 catalytic residues of the protein. Successively, their molecular mechanics Poisson Boltzmann surface area (MMPBSA) binding energies are calculated over the simulation trajectory to determine the dynamic atomistic interaction details. Overall, this study proposes two key natural chemical moieties: (a) tetrazol and (b) phenylpyrazol that can be investigated as a potential chemical group to design inhibitors against SARS-CoV2 RdRp.
| S-EPMC8742708 | biostudies-literature
Project description:The outbreak of SARS-CoV-2 in December 2019 in China subsequently lead to a pandemic. Lack of vaccine and specific anti-viral drugs started a global health disaster. For a sustained control and protection, development of potential anti-viral drugs is one of the targeted approach. Although, designing and developing a panel of new drugs molecules are always encouraged. However, in the current emergency, drug repurposing study is one of the most effective and fast track option. The crystal structure of a SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) RNA Dependent RNA Polymerase (RdRp) has recently been deciphered through X-ray crystallography. The single-chain of core RNA Dependent RNA Polymerase relies on virus-encoded cofactors nsp7 and two units of nsp8 for its optimum function. This study explored the FDA approved database of 7922 molecules and screened against the core polymerase along with cofactors. Here we report a panel of FDA approved drugs that show substantial interactions with key amino acid residues of the active site. Interestingly, some of the identified drugs (Ornipressin, Lypressin, Examorelin, Polymyxin B1) bind strongly within the binding pockets of both forms of RdRp. Besides, we found strong candidates for the complex form as well which include Nacortocin, Cistinexine, Cisatracurium (among others). These drugs have the potential to be considered while contriving therapeutic options.
| S-EPMC7377705 | biostudies-literature
Project description:An increasing number of studies have demonstrated the antiviral nature of polyphenols, and many polyphenols have been proposed to inhibit SARS-CoV or SARS-CoV-2. Our previous study revealed the inhibitory mechanisms of polyphenols against DNA polymerase α and HIV reverse transcriptase to show that polyphenols can block DNA elongation by competing with the incoming NTPs. Here we applied computational approaches to examine if some polyphenols can also inhibit RNA polymerase (RdRp) in SARS-CoV-2, and we identified some better candidates than remdesivir, the FDA-approved drug against RdRp, in terms of estimated binding affinities. The proposed compounds will be further examined to develop new treatments for COVID-19.
| S-EPMC8706955 | biostudies-literature
Project description:Dengue virus, an ?10.7-kb positive-sense RNA virus, is the most common arthropod-communicated pathogen in the world. Despite dengue's clear epidemiological importance, mechanisms for its replication remain elusive. Here, we probed the entire dengue genome for interactions with viral RNA-dependent RNA polymerase (RdRp), and we identified the dominant interaction as a loop-forming ACAG motif in the 3' positive-stranded terminus, complicating the prevailing model of replication. A subset of interactions coincides with known flaviviral recombination sites inside the viral protein-coding region. Specific recognition of the RNA element occurs via an arginine patch in the C-terminal thumb domain of RdRp. We also show that the highly conserved nature of the consensus RNA motif may relate to its tolerance to various mutations in the interacting region of RdRp. Disruption of the interaction resulted in loss of viral replication ability in cells. This unique RdRp-RNA interface is found throughout flaviviruses, implying possibilities for broad disease interventions.
| S-EPMC5016140 | biostudies-literature
Project description:IntroductionDespite all the efforts to treat COVID-19, no particular cure has been found for this virus. Since developing antiviral drugs is a time-consuming process, the most effective approach is to evaluate the approved and under investigation drugs using in silico methods. Among the different targets within the virus structure, as a vital component in the life cycle of coronaviruses, RNA-dependent RNA polymerase (RdRP) can be a critical target for antiviral drugs. The impact of the existence of RNA in the enzyme structure on the binding affinity of anti-RdRP drugs has not been investigated so far.MethodsIn this study, the potential anti-RdRP effects of a variety of drugs from two databases (Zinc database and DrugBank) were evaluated using molecular docking. For this purpose, the newly emerged model of COVID-19 (RdRP) post-translocated catalytic complex (PDB ID: 7BZF) that consists of RNA was chosen as the target.ResultsThe results indicated that idarubicin (IDR), a member of the anthracycline antibiotic family, and fenoterol (FNT), a known beta-2 adrenergic agonist drug, tightly bind to the target enzyme and could be used as potential anti-RdRP inhibitors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These outcomes revealed that due to the ligand-protein interactions, the presence of RNA in this structure could remarkably affect the binding affinity of inhibitor compounds.ConclusionIn silico approaches, such as molecular docking, could effectively address the problem of finding appropriate treatment for COVID-19. Our results showed that IDR and FNT have a significant affinity to the RdRP of SARS-CoV-2; therefore, these drugs are remarkable inhibitors of coronaviruses.
| S-EPMC7895701 | biostudies-literature
Project description:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) is a promising target for antiviral drugs. In this study, a chemical library (n = 300) was screened against the nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain. Blind docking was performed using a selection of 30 compounds and nine ligands were chosen based on their docking scores, safety profile, and availability. Using cluster analysis on a 10 microsecond molecular dynamics simulation trajectory (from D.E. Shaw Research), the compounds were docked to the different conformations. On the basis of our modelling studies, oleuropein was identified as a potential lead compound.
| S-EPMC8273049 | biostudies-literature
Project description:New treatment against SARS-CoV-2 now is a must. Nowadays, the world encounters a huge health crisis by the COVID-19 viral infection. Nucleotide inhibitors gave a lot of promising results in terms of its efficacy against different viral infections. In this work, molecular modeling, docking, and dynamics simulations are used to build a model for the viral protein RNA-dependent RNA polymerase (RdRp) and test its binding affinity to some clinically approved drugs and drug candidates. Molecular dynamics is used to equilibrate the system upon binding calculations to ensure the successful reproduction of previous results, to include the dynamics of the RdRp, and to understand how it affects the binding. The results show the effectiveness of Sofosbuvir, Ribavirin, Galidesivir, Remdesivir, Favipiravir, Cefuroxime, Tenofovir, and Hydroxychloroquine, in binding to SARS-CoV-2 RdRp. Additionally, Setrobuvir, YAK, and IDX-184, show better results, while four novel IDX-184 derivatives show promising results in attaching to the SARS-CoV-2 RdRp. There is an urgent need to specify drugs that can selectively bind and subsequently inhibit SARS-CoV-2 proteins. The availability of a punch of FDA-approved anti-viral drugs can help us in this mission, aiming to reduce the danger of COVID-19. The compounds 2 and 3 may tightly bind to the SARS-CoV-2 RdRp and so may be successful in the treatment of COVID-19.
| S-EPMC7222627 | biostudies-literature