In-silico study MM/GBSA binding free energy and molecular dynamics simulation of some designed remdesivir derivatives as the inhibitory potential of SARS-CoV-2 main protease

Background and purpose: Coronavirus disease (COVID-19) is one of the greatest challenges of the twentieth century. Recently, in silico tools help to predict new inhibitors of SARS-CoV-2. In this study, the new compounds based on the remdesivir structure (12 compounds) were designed. Experimental approach: The main interactions of remdesivir and designed compounds were investigated in the 3CLpro active site. The binding free energy of compounds by the MM-GBSA method was calculated and the best compound (compound 12 with the value of -88.173 kcal/mol) was introduced to the molecular dynamics simulation study. Findings/Results: The simulation results were compared with the results of protein simulation without the presence of an inhibitor and in the presence of remdesivir. Additionally, the RMSD results for the protein backbone showed that compound 12 in the second 50 nanoseconds has less fluctuation than the protein alone and in the presence of remdesivir, which indicates the stability of the compound in the active site of the Mpro protein. Furthermore, protein compactness was investigated in the absence of compounds and the presence of compound 12 and remdesivir. The Rg diagram shows a fluctuation of approximately 0.05 Å, which indicates the compressibility of the protein in the presence and absence of compounds. The results of the RMSF plot also show the stability of essential amino acids during protein binding. Conclusion and implications: Supported by the theoretical results, compound 12 could have the potential to inhibit the 3CLpro enzyme, which requires further in vitro studies and enzyme inhibition must also be confirmed at protein levels.