The coronavirus disease 2019 (COVID-19) pandemic has already taken a death toll of 169151 people and infected over 2475723 across the globe, as of April 22, 2020. The coronavirus (CoV), named Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), affects the respiratory tract leading to cough, fever, shortness of breath and pneumonia, and the patients often need life support systems [1]. Ever since the first case was reported in December (2019) from Wuhan (Hubei province, China) [2], the researchers across the globe are striving to develop a therapeutic intervention to control the pandemic. However, instead of the time consuming de novo drug discovery, repurposing of the approved drugs have been investigated [3]. This has been facilitated by elucidation of the viral genome sequence and protein/enzyme structures, which are the basis for drug discovery researches [4-5]. Further, knowledge gathered from studies on other related viruses including SARS-CoV, MERS-CoV and Hepatitis C virus (HCV), have been of great use. Molecular modeling (including molecular docking) tools have been the most useful tools in identifying potential drugs against COVID-19.
Following entry into host cell, the viral RNA encodes two polyproteins (pp1a and pp1ab) which are subsequently cleaved into non-structured proteins (NSPs) by two viral cysteine proteases, viz. the main protease (3CLpro) and Papain-like protease (PLPro), resulting in the formation of replication-transcription complex [6]. As innate immune defense against the virus, host produces interferon (IFN) through a cascade of reactions requiring ubiquitination and ISGylation of signaling molecules [7-9]. The PLPro of SARS-CoV has been reported to have IFN antagonistic activity (see [10] for details), the mechanism of which was found to be deubiquitination and deISGylation of signal molecules involved in the formation of IFN [11-12]. Thus, inhibition of PLPro remains to be one of the most attractive drug targets against CoVs including SARS-CoV, MERS-CoV and implicated for SARS-CoV-2 as well.
The preset study aims at identifying different compounds, including FDA approved drugs, drugs under clinical trials against different viruses or other pathogens, and natural products, which may potentially inhibit the PLPro of the SARS-CoV-2, using molecular modeling, so as to be repurposed against the virus. The aim was thus to identify and suggest possible PLPro inhibitors which may be used for clinical trials on COVID-19 patients. So far, three other such studies exist, one published and two in Preprint [13-15]. However, these studies used homology modeling to predict the structure of the protease for the want of the actual structure of the PLPro of the SARS-CoV-2. This might be one of the reasons that although the studies used similar methodologies, the results in terms of the drugs they reported as inhibitors of PLPro were different. Thus, ours is the first study using the PLPro of the SARS-CoV-2 deciphered very recently, and thus is highly significant.