Remdesivir Strongly Binds to RNA-Dependent RNA Polymerase, Membrane Protein, and Main Protease of SARS-CoV-2: Indication From Molecular Modeling and Simulations

Abstract

Development of new drugs is a time-taking and expensive process. Comprehensive efforts are being made globally toward the search of therapeutics against SARS-CoV-2. Several drugs such as remdesivir, favipiravir, ritonavir, and lopinavir have been included in the treatment regimen and shown effective results in several cases. Among the existing broad-spectrum antiviral drugs, remdesivir is found to be more effective against SARS-CoV-2. Remdesivir has broad-spectrum antiviral action against many single-stranded RNA viruses including pathogenic SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). In this study, we proposed that remdesivir strongly binds to membrane protein (Mprotein), RNA-dependent RNA polymerase (RDRP), and main protease (Mprotease) of SARS-CoV-2. It might show antiviral activity by inhibiting more than one target. It has been found that remdesivir binds to Mprotease, Mprotein, and RDRP with −7.8, −7.4, and −7.1 kcal/mol, respectively. The structure dynamics study suggested that binding of remdesivir leads to unfolding of RDRP. It has been found that strong binding of remdesivir to Mprotein leads to decrease in structural deviations and gyrations. Additionally, the average solvent-accessible surface area of Mprotein decreases from 127.17 to 112.12 nm2, respectively. Furthermore, the eigenvalues and the trace of the covariance matrix were found to be low in case of Mprotease–remdesivir, Mprotein–remdesivir, and RDRP–remdesivir. Binding of remdesivir to Mprotease, Mprotein, and RDRP reduces the average motions in protein due to its strong binding. The MMPBSA calculations also suggested that remdesivir has strong binding affinity with Mprotein, Mprotease, and RDRP. The detailed analysis suggested that remdesivir has more than one target of SARS-CoV-2.

Significance of Immune Status of SARS-CoV-2 Infected Patients in Determining the Efficacy of Therapeutic Interventions

“…Targets for remdesivir also include membrane protein (M protein) and RDRP inhibitors. It is the first drug approved clinically and repurposed as a potent antiviral agent for treating SARS-CoV-2 infected patients [ 76 , 77 ]. A well-recognized host protease inhibitor, including camostat mesylate and nafamostat, was useful in inhibiting the host TMPRSS-2 protease that restricts the entry of SARS-CoV-2 viruses into target host cells [ 78 ].…”

Evolution of SARS-CoV-2 in Spain during the First Two Years of the Pandemic: Circulating Variants, Amino Acid Conservation, and Genetic Variability in Structural, Non-Structural, and Accessory Proteins

“…The residues of the SARS-CoV-2 main protease (nsp5) involved in binding for remdesivir and Paxlovid (two antivirals recommended by the WHO for COVID-19 treatment in patients at risk of hospital admission) were highly conserved in our sequence dataset, with a percentage of mutated sequences below 0.2%. Some of these residues are involved in the binding of both drugs (C145, E166, H163, H164, Q192), while G143 is involved in Paxlovid binding, and other sites interact with remdesivir (H41, M49, Y54, F140, N142, S144, M165, L167, P168, H172, N187, R188, Q189, T190, and A191) [ 110 , 111 ]. We only found one sequence with a deletion in residue 192 (involved in the binding of both drugs) and no other aa changes in the rest of the sites that interact with Paxlovid, which showed complete conservation among the whole Spanish sequence dataset.…”

The Molecular Basis of the Effect of Temperature on the Structure and Function of SARS-CoV-2 Spike Protein

“…Recently, several inhibitors and their mode of action have been demonstrated ( Khan et al, 2021c ; Rani et al, 2021 ). Edwards et al found that the spike protein samples kept at diverse temperatures did not show any considerable denaturation, while they observed an increase in upper molecular weight bands in a sample that was kept at 37°C ( Edwards et al, 2021 ).…”