An integrated drug repurposing strategy for the rapid identification of potential SARS-CoV-2 viral inhibitors

Abstract

The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein-ACE2 interaction inhibitor. Our data showed that Simeprevir and Lumacaftor bind the receptorbinding domain of the Spike protein with high affinity and prevent ACE2 interaction. The World Health Organisation (WHO) declared the Coronavirus disease (COVID-19) outbreak a pandemic on March 12th 2020, and as of May 21st, over 4,893,186 cases and 323,256 deaths have been reported (https :// www.who.int/emerg encie s/disea ses/novel-coron aviru s-2019/situa tion-repor ts/). The Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) was identified as the viral agent causing the disease. SARS-CoV-2 is closely related to the SARS-CoV, which caused a pandemic in 2002-2003 1 , and it is believed to be the third member of the Coronaviridae family to cause severe respiratory diseases in human 2. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. SARS-CoV-2 has a single-stranded positive-sense RNA composed of 29,903 nt containing five genes, ORF1ab (codifying 16 non-structural proteins), spike (S), envelope (E), membrane (M) and nucleocapsid (N) genes 3. The virus uses the S homotrimeric glycoprotein located on the virion surface to allow entry into the human cells 4. The S protein goes through major structural rearrangements to mediate viral and human cell membranes fusion. The process is initiated by the binding of the receptor-binding domain (RBD) of the S1 subunit to the peptidase domain (PD) of angiotensin-converting enzyme 2 receptor (ACE2) on the host cell 5. Structural studies have shown that two S protein trimers can simultaneously bind to one ACE2 dimer 6. This induces a conformational change that expose a proteolytic site on the S protein, which is cleaved by the cellular serine protease TMPRSS2 7. Dissociation of S1 induces transition of the S2 subunit to a post fusion conformation, with exposed fusion peptides 8 , which allows endocytic entry of virus 9. Wrapp et ...

Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2in Vitro

“…It should be noted that simeprevir was also described to impact cellular innate immune responses 61 and Spike, were suggested for paritaprevir, grazoprevir and simeprevir by modelling studies. 53,67,[78][79][80][81][82] Future detailed molecular studies are required to fully define the viral targets of different HCV preprint (which was not certified by peer review) is the author/funder. All rights reserved.…”

Insilico drug repurposing using FDA approved drugs against Membrane protein of SARS-CoV-2

“…Remdesivir can bind both the proteins efficiently and hence found most effective against SARS-CoV-2 infections. The concept of multi-target drugs which can target multiple proteins simultaneously has been already in use and found effective and hence Remdesivir can be selected as a hit against M-protein 78 . The Bafilomycin A1 is reported to inhibit SARS-CoV-2…”

A COVID-19 Drug Repurposing Strategy through Quantitative Homological Similarities Using a Topological Data Analysis-Based Framework

“…Additionally, transcriptomic data represent a rich alternative resource for inferring non-obvious relationships between drugs and genes. Previous in silico molecular docking studies have highlighted the potential of repurposed drugs for the treatment of COVID-19 [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. However, here we used in silico molecular docking combined with transcriptomic small molecule treatment data from LINCS L1000 to determine which FDA-approved drugs may reverse the effects of SARS-CoV-2 infection.…”