Exploring RdRp–remdesivir interactions to screen RdRp inhibitors for the management of novel coronavirus 2019-nCoV

Abstract

A novel coronavirus recently identified in Wuhan, China (2019-nCoV) has resulted in an increasing number of patients globally, and has become a highly lethal pathogenic member of the coronavirus family affecting humans. 2019-nCoV has established itself as one of the most threatening pandemics that human beings have faced, and therefore analysis and evaluation of all possible responses against infection is required. One such strategy includes utilizing the knowledge gained from the SARS and MERS outbreaks regarding existing antivirals. Indicating a potential for success, one of the drugs, remdesivir, under repurposing studies, has shown positive results in initial clinical studies. Therefore, in the current work, the authors have attempted to utilize the remdesivir–RdRp complex – RdRp (RNA-dependent RNA polymerase) being the putative target for remdesivir – to screen a library of the already reported RdRp inhibitor database. Further clustering on the basis of structural features and scoring refinement was performed to filter out false positive hits. Finally, molecular dynamics simulation was carried out to validate the identification of hits as RdRp inhibitors against novel coronavirus 2019-nCoV. The results yielded two putative hits which can inhibit RdRp with better potency than remdesivir, subject to further biological evaluation.

Phenolic compounds as antiviral agents: An In-Silico investigation against essential proteins of SARS-CoV-2

“…It was found that the three ligands interact with u20 (P), a19 (P) from the RNA nucleotides and with Asn691 (A), Ser759 (A), Arg836 (A), Val557 (A), Arg555 (A) from the RdRp residues. These findings are in accordance with the work of Singh et al (2020) who observed that Remdesivir (an FDA-approved intravenous antiviral drug) maintained key H-bond interaction with u20 from RNA nucleotides and having a binding pocket amino acid residue including Arg553, Arg555, Thr556 and Asn691, explaining its potential inhibitory effect. Moreover, Bastikar et al (2020) reported that the docking results of curcumin and allicin derivatives with RNA dependent RNA polymerase showed good binding affinity and having interactions with U10, A11 and U20 nucleotides and amino acid residues such as Asp623, Asn691, Arg555 and Ser682 which are highly involved in the hydrogen bonding with most of the tested ligands.…”

Computational methods directed towards drug repurposing for COVID-19: advantages and limitations

“… 14 Singh et al , screened >350 potential RdRp (PDB: ) inhibitors from the BRENDA library and proposed IN-6 and IN-17 as two promising hits compounds with the potential to inhibit RdRp with enhanced potency than remdesivir ( Table 1 ). 36 These two molecules maintained interaction with key residues K551, R553, R555, and T556. Alectinib is also proposed as a promising RdRp inhibitor, which was first used for non-small cell lung cancer (NSCLC) treatment.…”

RdRp (RNA-dependent RNA polymerase): A key target providing anti-virals for the management of various viral diseases

“…With the advancements in current tools and techniques, all the essential proteins targeted to develop anti-virals are well-known. Still, RNA-dependent RNA polymerases (RdRps) remain among the most critical viral drug targets [ 13 , 14 ]. It is involved in the genome replication process of an RNA from an RNA template, which is then involved in the encoding of some of the important proteins for the proper functioning and survival of viruses [15] .…”