Fullerenes against COVID-19: Repurposing C(60) and C(70) to Clog the Active Site of SARS-CoV-2 Protease

The persistency of COVID-19 in the world and the continuous rise of its variants demand new treatments to complement vaccines. Computational chemistry can assist in the identification of moieties able to lead to new drugs to fight the disease. Fullerenes and carbon nanomaterials can interact with proteins and are considered promising antiviral agents. Here, we propose the possibility to repurpose fullerenes to clog the active site of the SARS-CoV-2 protease, M(pro). Through the use of docking, molecular dynamics, and energy decomposition techniques, it is shown that C(60) has a substantial binding energy to the main protease of the SARS-CoV-2 virus, M(pro), higher than masitinib, a known inhibitor of the protein. Furthermore, we suggest the use of C(70) as an innovative scaffold for the inhibition of SARS-CoV-2 M(pro). At odds with masitinib, both C(60) and C(70) interact more strongly with SARS-CoV-2 M(pro) when different protonation states of the catalytic dyad are considered. The binding of fullerenes to M(pro) is due to shape complementarity, i.e., vdW interactions, and is aspecific. As such, it is not sensitive to mutations that can eliminate or invert the charges of the amino acids composing the binding pocket. Fullerenic cages should therefore be more effective against the SARS-CoV-2 virus than the available inhibitors such as masinitib, where the electrostatic term plays a crucial role in the binding.