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

• Published in: SAR and QSAR in environmental research Vol. 31; no. 11; pp. 857 - 867
• Main Authors: Singh, P.K., Pathania, S., Rawal, R.K.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01-11-2020; Taylor & Francis Ltd
• Subjects: Adenosine Monophosphate - analogs & derivatives; Adenosine Monophosphate - chemistry; Adenosine Monophosphate - pharmacology; Alanine - analogs & derivatives; Alanine - chemistry; Alanine - pharmacology; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Betacoronavirus - drug effects; Betacoronavirus - enzymology; Clustering; Coronaviridae; Coronavirus Infections - drug therapy; Coronaviruses; COVID-19; DNA-directed RNA polymerase; Inhibitors; molecular docking; Molecular Docking Simulation; Molecular dynamics; Pandemics; Pneumonia, Viral; Quantitative Structure-Activity Relationship; Remdesivir-RdRp complex; RNA polymerase; RNA-Dependent RNA Polymerase - antagonists & inhibitors; RNA-directed RNA polymerase; SARS-CoV-2; scoring refinement; Viral diseases; Viral Proteins - drug effects; COVID-19; scoring refinement; Remdesivir–RdRp complex; molecular docking; molecular dynamics
• ISSN: 1062-936X; 1029-046X
• DOI: 10.1080/1062936X.2020.1825014

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.