Abstract
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.
Highlights
The ongoing COVID-19 pandemic, which emerged in China at the end of 2019, is caused by the third severely pathogenic novel coronavirus since the beginning of the twenty-first century
In molecular dynamics (MD) simulation of the rac5c-papain-like protease (PLpro) complex we found that rac5c was stably bound inside the PLpro’s pocket for the entire ∼450 ns simulation
Due to the urgency of the pandemic, drug repurposing might provide an immediate and temporary solution with already known safety and PK profiles of each approved drug. Both our in silico and previous in vitro (Klemm et al, 2020) studies suggest that drug repurposing might not be a viable way to discover efficacious inhibitors for PLpro
Summary
The ongoing COVID-19 pandemic, which emerged in China at the end of 2019, is caused by the third severely pathogenic novel coronavirus since the beginning of the twenty-first century. This new virus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is similar to, yet distinct from, the previous two zoonotic coronaviruses, SARS-CoV and MERS-CoV, which caused serious and atypical pneumonia (Kuiken et al, 2003; Bermingham et al, 2012; Wu et al, 2020). Most COVID-19 infected individuals will only have mild symptoms (or no symptoms at all) Those with certain underlying health conditions (such as cardiovascular disease, chronic respiratory disease, or diabetes) can become severely sick with fatal outcomes. As the entire world battles this pandemic, scientists and Exploring Inhibitors for Popain-Like Protease
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