Abstract
The outbreak of a new coronavirus SARS-CoV-2 (severe acute respiratory syndrome–coronavirus 2) has caused a global COVID-19 (coronavirus disease 2019) pandemic, resulting in millions of infections and thousands of deaths around the world. There is currently no drug or vaccine for COVID-19, but it has been revealed that some commercially available drugs are promising, at least for treating symptoms. Among them, remdesivir, which can block the activity of RNA-dependent RNA polymerase (RdRp) in old SARS-CoV and MERS-CoV viruses, has been prescribed to COVID-19 patients in many countries. A recent experiment showed that remdesivir binds to SARS-CoV-2 with an inhibition constant of μM, but the exact target has not been reported. In this work, combining molecular docking, steered molecular dynamics, and umbrella sampling, we examined its binding affinity to two targets including the main protease (Mpro), also known as 3C-like protease, and RdRp. We showed that remdesivir binds to Mpro slightly weaker than to RdRp, and the corresponding inhibition constants, consistent with the experiment, fall to the μM range. The binding mechanisms of remdesivir to two targets differ in that the electrostatic interaction is the main force in stabilizing the RdRp–remdesivir complex, while the van der Waals interaction dominates in the Mpro–remdesivir case. Our result indicates that remdesivir can target not only RdRp but also Mpro, which can be invoked to explain why this drug is effective in treating COVID-19. We have identified residues of the target protein that make the most important contribution to binding affinity, and this information is useful for drug development for this disease.
Highlights
An outbreak of a new coronavirus appeared in Wuhan, China, at the end of 2019 and is spreading rapidly in many countries,[1,2] resulting in a pandemic announced by WHO in March 2020.3,4 2019 coronavirus disease (COVID-19) causes severe acute respiratory syndrome (SARS) with pathological symptoms such as coughing, fever, shortness of breath, and pneumonia,[5] and critically ill patients may develop a cytokine storm syndrome.[6−8] Compared to the 2002 SARS epidemic caused by SARS coronavirus (SARS-CoV), the COVID-19 mortality rate is lower,[9] but the number of infected cases and deaths is much higher.[2]
Our result indicates that remdesivir can target RNA-dependent RNA polymerase (RdRp) and main protease (Mpro), which can be invoked to explain why this drug is effective in treating COVID-19
We have studied the association of remdesivir with RdRp and Mpro
Summary
An outbreak of a new coronavirus appeared in Wuhan, China, at the end of 2019 and is spreading rapidly in many countries,[1,2] resulting in a pandemic announced by WHO in March 2020.3,4 2019 coronavirus disease (COVID-19) causes severe acute respiratory syndrome (SARS) with pathological symptoms such as coughing, fever, shortness of breath, and pneumonia,[5] and critically ill patients may develop a cytokine storm syndrome.[6−8] Compared to the 2002 SARS epidemic caused by SARS coronavirus (SARS-CoV), the COVID-19 mortality rate is lower,[9] but the number of infected cases and deaths is much higher.[2]. Regarding the mechanism of infection and pathogenicity of SARS-CoV-2, proteases play an important role in viral structure assembly and replication.[25,26] In coronaviruses, ORF1a encodes a main protease (Mpro) (Figure 1), which is called a chymotrypsin-like cysteine protease (3CLPro).[27,28] Mpro has a mass of about 33.8 kDa and is embedded in the nsp[5] region, which is encoded by the SARSCoV-2 RNA sequence (Figure 1, upper part). The substrate binding site of Mpro is situated between domains I and II, in which residues His[41] and Cys[145] are dominant in catalytic activity.[33−36] Mpro plays a key role in coordinating viral replication and transcription of the virus life cycle It cleaves the major part of polyproteins and releases proteins that have replicative function such as RdRp and RNAprocessing domains.[37] Mpro becomes a prime target for drugs for SARS-CoV-2.38,39.
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