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Remdesivir Strongly Binds to both RNA-dependent RNA Polymerase and Main Protease of SARS-CoV-2: Evidence from Molecular Simulations

preprint
submitted on 07.08.2020 and posted on 10.08.2020 by Hoang Linh Nguyen, Thai Nguyen, Duc Toan Truong, Mai Suan Li
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 electrostatic interaction is the main force in stabilizing the RdRp-Remdesivir complex, while the van der Waals interaction dominates in the MproRemdesivir 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.

History

Email Address of Submitting Author

hoanglinh221191@gmail.com

Institution

ho chi minh city institute for computational science and technology

Country

Vietnam

ORCID For Submitting Author

0000-0003-4141-1642

Declaration of Conflict of Interest

no conflict of interest

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