Potential inhibitors for 2019-nCoV coronavirus M protease from clinically approved medicines

Abstract

Starting from December 2019, a novel coronavirus, named 2019-nCoV, was found to cause Severe Acute Respiratory (SARI) symptoms and rapid pandemic in China.With the hope to identify candidate drugs for 2019-nCoV, we adopted a computational approach to screen for available commercial medicines which may function as inhibitors for the M pro of 2019-nCoV. Up to 10 commercial medicines that may form hydrogen bounds to key residues within the binding pocket of 2019-nCoV M pro were identified, which may have higher mutation tolerance than lopinavir/ritonavir and may also function as inhibitors for other coronaviruses with similar M pro binding sites and pocket structures. Coronaviruses, members of the family Coronaviridae and subfamilyCoronavirinae, are enveloped positive-stranded RNA viruses which have spikes of glycoproteins projecting from their viral envelopes, thus exhibit a corona or halo-like appearance (Masters and Perlman, 2013; Cui et al., 2019) Coronaviruses are the causal pathogens for a wide spectrum of respiratory and gastrointestinal diseases in both wild and domestic animals, including birds, pigs, rodents, etc (Dhama et al., 2014). Previous studies have found that six strains of coronaviruses are capable to infect human, author/funder. All rights reserved. No reuse allowed without permission.

The deadly coronaviruses: The 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China

“…Based on the structural information of clinical effective medicines for SARS-CoV-2, Liu et al predicted 10 commercial medicines which may function as inhibitors of SARS-CoV-2, including colistin, valrubicin, icatibant, bepotastine, epirubicin, etc. Some of these may be more resistant to viral mutation than lopinavir/ritonavir [133]. Stebbing et al suggested that baricitinib may reduce both the viral entry and inflammation [134].…”

Structural and Evolutionary Analysis Indicate that the SARS-CoV-2 Mpro is an Inconvenient Target for Small-Molecule Inhibitors Design

“…The lack of success might be related to the above-mentioned plasticity of the binding cavity. Some of these compounds have been used for docking and virtual screening research aimed not only at SARS-CoV [42,43] but also at the novel SARS-CoV-2 [15][16][17][18][19][20][21]. Such an approach focuses mostly on the structural similarity between the binding pockets, but ignores the fact that the actual available binding space differs significantly.…”

“…Indeed, an in silico attempt has already been made involving a massive virtual screening for Mpro inhibitors of SARS-CoV-2 using Deep Docking [15]. Other recent attempts focused on virtual screening for putative inhibitors of the same main protease of SARS-CoV-2 based on the clinically approved drugs [16][17][18][19][20][21], and also based on the compounds from different databases or libraries [22][23][24]. However, none of such attempts is likely to lead to clinical advances in the fight against SARS-CoV-2 for reasons we elaborate below.…”

Coronavirus disease 2019 (COVID-19): A literature review

“…Ramsedivir, a broad spectrum antivirus has demonstrated in vitro and in vivo efficacy against SARS-CoV-2 and has also initiated its clinical trial [63,64]. In addition, other potential drugs from existing antiviral agent have also been proposed [65,66].…”