Towards the discovery of potential RdRp inhibitors for the treatment of COVID-19: structure guided virtual screening, computational ADME and molecular dynamics study

Abstract

Coronavirus disease 2019 (COVID-19) has become a major challenge affecting almost every corner of the world, with more than five million deaths worldwide. Despite several efforts, no drug or vaccine has shown the potential to check the ever-mutating SARS-COV-2. The emergence of novel variants is a major concern increasing the need for the discovery of novel therapeutics for the management of this pandemic. Out of several potential drug targets such as S protein, human ACE2, TMPRSS2 (transmembrane protease serine 2), 3CLpro, RdRp, and PLpro (papain-like protease), RNA-dependent RNA polymerase (RdRP) is a vital enzyme for viral RNA replication in the mammalian host cell and is one of the legitimate targets for the development of therapeutics against this disease. In this study, we have performed structure-based virtual screening to identify potential hit compounds against RdRp using molecular docking of a commercially available small molecule library of structurally diverse and drug-like molecules. Since non-optimal ADME properties create hurdles in the clinical development of drugs, we performed detailed in silico ADMET prediction to facilitate the selection of compounds for further studies. The results from the ADMET study indicated that most of the hit compounds had optimal properties. Moreover, to explore the conformational dynamics of protein–ligand interaction, we have performed an atomistic molecular dynamics simulation which indicated a stable interaction throughout the simulation period. We believe that the current findings may assist in the discovery of drug candidates against SARS-CoV-2.

Ligand- and Structure-Based Virtual Screening Identifies New Inhibitors of the Interaction of the SARS-CoV-2 Spike Protein with the ACE2 Host Receptor

“…However, there are no more recent reports related to clinical studies. In the case of the compound DRI-5, in 2022, through SBVS studies, this molecule was proposed as a potential agent to treat COVID-19 targeting SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) [35]. Despite this, in vitro validation still is not demonstrated.…”

Targeting RdRp of SARS-CoV-2 with De Novo Molecule Generation

“…Successful attempts were made previously by computational studies to find the Repurposing drug molecules in the literature that can efficiently bind to SARS-CoV-2 targets. − Among several possible targets, including spike protein, main protease (M pro ), etc., RdRp is a promising target for drug design. Some antiviral molecules have already been identified by targeting key residues in the active site of RdRp and other proteins involved in the lifecycle of the virus. − At the same time, various drug repurposing studies that target RdRp using computational tools like docking have also been reported. − All of these studies resulted in a great number of possible drugs that could be repurposed for the treatment of COVID-19, pending rigorous theoretical or experimental tests.…”