Evaluation of potential anti-RNA-dependent RNA polymerase (RdRP) drugs against the newly emerged model of COVID-19 RdRP using computational methods

Abstract

Introduction Despite 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. Methods In 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. Results The 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. Conclusion In 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.

Tenofovir, Another Inexpensive, Well-Known and Widely Available Old Drug Repurposed for SARS-COV-2 Infection

“…As reviewed in this work, several in silico studies suggest the inhibitory activity of tenofovir and its derivative prodrugs TDF and TAF on their presumed and more obvious viral target, the SARS-CoV-2 RdRp protein, likely competing with the natural nucleotide adenosine for the enzyme binding and then acting as chain terminators [ 50 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 ]. Notably, in one of these studies [ 81 ] a better binding activity of tenofovir with the P323L mutated RdRp protein was observed in comparison with remdesivir, further suggesting tenofovir use in COVID-19 treatment.…”

“…Similar findings were obtained by Udofia et al [ 73 ], using Sars-CoV-2 and Sars-CoV RdRp and Mpro/3CLpro as targets for 173 compounds and performing molecular docking in which the protein structures were kept rigid while ligands were allowed full rotations. Poustforoosh and colleagues [ 74 ] virtually screened 28 compounds against two active sites of RdRp by rigid and induced-fit docking, and found that tenofovir had lower docking scores than other tested drugs. Similar findings were obtained by Tiwari [ 75 ].…”

Introducing a novel chemotherapeutic drug formulated with anthraflavic acid for treating human breast carcinoma and type 2 diabetes mellitus

“…The minimization step was ten applied for the structure using optimized potentials for liquid simulations (OPLS3e) force field. The binding sites of the enzyme were predicted using the SiteMape of Schrödinger to find the active sites of the structure [13]. The SDF files of the anthraflavic acid and acarbose were gained from the PubChem database and the correct molecular geometrics were generated utilizing the LigPrep module of Schrödinger [14].…”

Alpinetin: anti-human gastric cancer potential and urease inhibition activity <i>in vitro</i>

“…Finally, the structure was subjected to minimization using the OPLS3e force field, and the prepared enzyme was used for the docking study. The binding site prediction was performed utilizing SiteMap of Schrödinger [16] to predict the active sites of the enzyme. After that, a grid box (20˟20˟20Å 3 ) was generated centroid of the predicted active site.…”