Drug Repurposing against SARS-CoV-2 RDRP - a computational quest against CoVID-19
Hirak Chakraborty, Prasenjit Paria, Aditi Gangopadhyay, Sayak Ganguli
Received date: 29th March 2020
The present CoVID-19 pandemic was first detected in December 2019 in Wuhan, China, and is rapidly spreading worldwide. To date, it has affected 465,915 individuals in 200 countries, and has been responsible for 21,031 deaths. In the absence of definitive treatment strategies, there is a pressing demand for drug discovery against CoVID-19. Drug repurposing is a cost-effective and time-saving strategy which essentially involves the identification of novel targets for known drug candidates. This reduces the time and cost of drug discovery, as the pharmacokinetics and toxicity profiles of the drugs are already known, which makes phase I clinical trials redundant. Here, we employed a computational drug repurposing strategy for identifying drug hits against the RNA-dependent RNA polymerase (RDRP) protein of CoVID-19. Analysis of the human-virus protein-protein associations revealed that the viral RDRP (NSP12) is associated with multiple host proteins that partake in cellular processes, which indicated that NSP12 could be a potential target for drug discovery. This, combined with the fact that the RDRP protein is a potential antiviral target in several viral diseases, led us to consider the NSP12 as a potential drug target for CoVID-19. Owing to the absence of an experimentally-derived structure in the PDB, we constructed the NSP12 protein of CoVID-19 by homology modelling, and the potential druggable sites were analysed. The 13,533 entries in DrugBank were initially screened using the sequence of CoVID-19 NSP12. The 7 hits thus identified were subjected to a consensus docking and scoring strategy for identifying hits against the druggable site of CoVID-19 NSP12. Analysis of the docking scores and protein-ligand interactions revealed that two hits – N-alpha-[(benzyloxy)carbonyl]-n-[(1r)-4-hydroxy-1-methyl-2-oxobutyl]-l-phenylalaninamide and S-[5-(trifluoromethyl)-4h-1,2,4-triazol-3-yl] 5-(phenylethynyl) furan-2 -carbothioate, had stronger binding affinity than remdesivir, which is being presently tested in clinical trials for its antiviral activity against CoVID-19. This indicated that these two compounds might be effective against CoVID-19, however, further experimentation is necessary for obtaining substantial evidence. We believe that the results of this study could offer a novel avenue for drug development against CoVID-19.
This is an abstract of a preprint hosted on a preprint server, which is currently undergoing peer review at Scientific Reports. The findings have yet to be thoroughly evaluated, nor has a decision on ultimate publication been made. Therefore, the results reported should not be considered conclusive, and these findings should not be used to inform clinical practice, or public health policy, or be promoted as verified information.