Artificially expanded genetic information systems (AEGISs) as potent inhibitors of the RNA-dependent RNA polymerase of the SARS-CoV-2

Abstract

The recent outbreak of the SARS-CoV-2 infection has affected the lives and economy of more than 200 countries. The unavailability of virus-specific drugs has created an opportunity to identify potential therapeutic agents that can control the rapid transmission of this pandemic. Here, the mechanisms of the inhibition of the RNA-dependent RNA polymerase (RdRp), responsible for the replication of the virus in host cells, are examined by different ligands, such as Remdesivir (RDV), Remdesivir monophosphate (RMP), and several artificially expanded genetic information systems (AEGISs) including their different sequences by employing molecular docking, MD simulations, and MM/GBSA techniques. It is found that the binding of RDV to RdRp may block the RNA binding site. However, RMP would acquire a partially flipped conformation and may allow the viral RNA to enter into the binding site. The internal dynamics of RNA and RdRp may help RMP to regain its original position, where it may inhibit the RNA-chain elongation reaction. Remarkably, AEGISs are found to obstruct the binding site of RNA. It is shown that dPdZ, a two-nucleotide sequence containing P and Z would bind to RdRp very strongly and may occupy the positions of two nucleotides in the RNA strand, thereby denying access of the substrate–binding site to the viral RNA. Thus, it is proposed that the AEGISs may act as novel therapeutic candidates against the SARS-CoV-2. However, in vivo evaluations of their potencies and toxicities are needed before using them against COVID-19.

Fluorinated oil-surfactant mixtures with the density of water: artificial cells for synthetic biology

“…Fluorine has an atomic mass of 19, meaning fluorinated molecules are intrinsically denser than water. However, this greater atomic mass can be partly offset by the larger mean volumes of CF 2 (38 Å 3 ) and CF 3 (92 Å 3 ) groups relative to CH 2 (27 Å 3 ) and CH 3 (54 Å 3 ) [31], both less dense than water. Therefore, we reasoned that fluorous oils having a density of water might be obtained by balancing their fluorinated components with alkane components.…”

“…Several of these are used to deliver drugs to cells in AEGISbodynanotrain-drug conjugates [29]. Modified nucleic acids can potentially be used as therapeutics [30]; recently some AEGIS components have been suggested as potential inhibitors of the RNA polymerase from SARS-CoV-2 [31]. Despite these applications, useful and robust water-in-oil systems have proven difficult to generate.…”

Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

“… 519 Nakinadine B and ormycalamide A were subjected to MM/GBSA studies in docking of 51 marine sponge metabolites to RdRp. 520 Sonousi et al 521 and Jena et al 522 evaluated the efficacy of adenosine derivatives and synthetic nucleotides to RdRp via docking and MM/GBSA calculations. Molecular docking, MD simulations, and MM/GBSA approaches have also been used to examine the role of several short ionic peptides in inhibiting RdRp.…”

C-Terminal Extended Hexapeptides as Potent Inhibitors of the NS2B-NS3 Protease of the ZIKA Virus

“…The PyMOL program (41) was used to create the mutated peptides. As these peptides were subjected to molecular dynamics simulations, it is believed that the mutated structures are not biased to their initial conformation (35,42,43).…”