In silico Drug Repurposing to combat COVID-19 based on Pharmacogenomics of Patient Transcriptomic Data

Abstract The ongoing global pandemic of coronavirus disease 2019 (COVID-19) continues to affect a growing number of populations in different parts of the world. In the current situation, drug repurposing is a viable strategy to combat COVID-19. The drugs targeting the host receptors that interact with SARS-CoV-2 are possible candidates. However, assessment of their effectiveness in COVID-19 patients is necessary before prioritizing them for further study. We attempted to shortlist the candidate drugs using an in-silico approach. First, we analysed two published transcriptomic data sets of COVID-19- and SARS-infected patients compared to healthy individuals to find the key pathways altered after infection. Then, using publicly available drug perturbational data sets in human cell lines from the Broad Institute Connectivity Map (CMAP), we assessed the effects of the approved drugs on the altered pathways. We also used the available pharmacogenomic data sets from the Genomics of Drug Sensitivity in Cancer (GDSC) portal to assess the effects of the altered pathways on resistance or sensitivity to the drugs in human cell lines. Our analysis identified many candidate drugs, some of which are already being investigated for treatment of COVID-19 and can serve as a basis for prioritizing additional viable candidate drugs for COVID-19.

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In silico Exploration of Inhibitors for SARS-CoV-2's Papain-Like Protease

Frontiers in Chemistry ◽

10.3389/fchem.2020.624163 ◽

2021 ◽

Vol 8 ◽

Author(s):

Tien Huynh ◽

Wendy Cornell ◽

Binquan Luan

Keyword(s):

Molecular Mechanism ◽

In Silico ◽

High Throughput Screening ◽

Docking Simulation ◽

Drug Repurposing ◽

Dynamics Simulation ◽

Global Pandemic ◽

Viral Maturation ◽

Approved Drugs ◽

Potential Inhibitors

Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with very limited treatments so far. Demonstrated with good druggability, two major proteases of SARS-CoV-2, namely main protease (Mpro) and papain-like protease (PLpro) that are essential for viral maturation, have become the targets for many newly designed inhibitors. Unlike Mpro that has been heavily investigated, PLpro is not well-studied so far. Here, we carried out the in silico high-throughput screening of all FDA-approved drugs via the flexible docking simulation for potential inhibitors of PLpro and explored the molecular mechanism of binding between a known inhibitor rac5c and PLpro. Our results, from molecular dynamics simulation, show that the chances of drug repurposing for PLpro might be low. On the other hand, our long (about 450 ns) MD simulation confirms that rac5c can be bound stably inside the substrate-binding site of PLpro and unveils the molecular mechanism of binding for the rac5c-PLpro complex. The latter may help perform further structural optimization and design potent leads for inhibiting PLpro.

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