In-silico study: docking simulation and molecular dynamics of peptidomimetic fullerene-based derivatives against SARS-CoV-2 M^pro

COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, has become a global pandemic resulting in significant morbidity and mortality. This study presents 12 new peptidomimetic fullerene-based derivatives in three groups that are investigated theoretically as SARS-CoV-2 M^pro inhibitors to increase the chance of treating COVID-19. Studied compounds are designed and optimized at B88-LYP/DZVP method. Molecular descriptors results show the stability and reactivity of the compounds with M^pro, especially in the 3rd group (Ser compounds). However, Lipinski's Rule of Five values indicates that the compounds are not suitable as oral drugs. Furthermore, molecular docking simulations are carried out to investigate the binding affinity and interaction modes of the top five compounds (compounds 1, 9, 11, 2, and 10) with the M^pro protein, which have the lowest binding energy. Molecular dynamics simulations are also performed to evaluate the stability of the protein–ligand complexes with compounds 1 and 9 and compare them with natural substrate interaction. The analysis of RMSD, H-bonds, Rg, and SASA indicates that both compounds 1 (Gly-α acid) and 9 (Ser-α acid) have good stability and strong binding affinity with the M^pro protein. However, compound 9 shows slightly better stability and binding affinity compared to compound 1.