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Remdesivir Strongly Binds to Both RNA-Dependent RNA Polymerase and Main Protease of SARS-CoV-2: Evidence from Molecular Simulations.
Nguyen, Hoang Linh; Thai, Nguyen Quoc; Truong, Duc Toan; Li, Mai Suan.
  • Nguyen HL; Life Science Lab, Institute for Computational Science and Technology, Quang Trung Software City, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City 700000, Vietnam.
  • Thai NQ; Life Science Lab, Institute for Computational Science and Technology, Quang Trung Software City, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City 700000, Vietnam.
  • Truong DT; Dong Thap University, 783 Pham Huu Lau Street, Ward 6, Cao Lanh City 870000, Dong Thap, Vietnam.
  • Li MS; Life Science Lab, Institute for Computational Science and Technology, Quang Trung Software City, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City 700000, Vietnam.
J Phys Chem B ; 124(50): 11337-11348, 2020 12 17.
Article in English | MEDLINE | ID: covidwho-1065784
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / RNA-Dependent RNA Polymerase / Adenosine Monophosphate / Alanine / Coronavirus 3C Proteases / SARS-CoV-2 Topics: Vaccines Limits: Humans Language: English Journal: J Phys Chem B Journal subject: Chemistry Year: 2020 Document Type: Article Affiliation country: Acs.jpcb.0c07312

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / RNA-Dependent RNA Polymerase / Adenosine Monophosphate / Alanine / Coronavirus 3C Proteases / SARS-CoV-2 Topics: Vaccines Limits: Humans Language: English Journal: J Phys Chem B Journal subject: Chemistry Year: 2020 Document Type: Article Affiliation country: Acs.jpcb.0c07312