Fullerenes against COVID-19: Repurposing C60 and C70 to Clog the Active Site of SARS-CoV-2 Protease

Abstract

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, Mpro. Through the use of docking, molecular dynamics, and energy decomposition techniques, it is shown that C60 has a substantial binding energy to the main protease of the SARS-CoV-2 virus, Mpro, higher than masitinib, a known inhibitor of the protein. Furthermore, we suggest the use of C70 as an innovative scaffold for the inhibition of SARS-CoV-2 Mpro. At odds with masitinib, both C60 and C70 interact more strongly with SARS-CoV-2 Mpro when different protonation states of the catalytic dyad are considered. The binding of fullerenes to Mpro 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.

Synthesis of [60]Fullerene Hybrids Endowed with Steroids and Monosaccharides: Theoretical Underpinning as Promising anti‐SARS‐CoV‐2 Agents

“…In similar studies Calvaresi et al [59a] . determined that the core of C 60 occludes the enzyme cavity and interacts directly with the catalytic residue H41 by π‐π stacking interactions.…”

Fullerene Derivatives for Drug Delivery against COVID-19: A Molecular Dynamics Investigation of Dendro[60]fullerene as Nanocarrier of Molnupiravir

“…Note that the unmodified C 60 fullerene molecule, which is highly lipophilic, according to experimental evidence presents an octanol-water partition coefficient of about 6.67 [ 55 ]. Unfortunately, since dendro[60]fullerene joined with molnupiravir is studied here for the first time, more focused comparisons with other relevant available studies [ 28 , 35 , 37 , 41 , 42 , 43 , 44 , 45 ] are not possible for the time being.…”

“…In order to reach clear conclusions, the dendro[60]fullerene alone is also tested in water and n-octanol environments to be compared with the proposed dendro[60]fullerene/molnupiravir molecules drug delivery system. Despite the fact that there are several reports [ 28 , 35 , 37 , 41 , 42 , 43 , 44 , 45 ] on the exploitation of the use of C 60 -based molecular systems against COVID-19, to the author’s best knowledge, this is the first time that dendro[60]fullerene has been proposed and tested as a possible nanovehicle of molnupiravir.…”

The Emergence of Carbon Nanomaterials as Effective Nano-Avenues to Fight against COVID-19

“…A few theoretical studies were carried out using density functional theory [ 65 ], docking and molecular dynamics [ 66 ], and energy decomposition techniques [ 67 ] to check the feasibility of using fullerene for inhibiting the coronavirus. The results revealed that, because of its hydrophobicity and stiffness, fullerene could minimize the factors that often oppose its binding with the SARS-CoV-2 virus, which makes fullerenes an excellent inhibitor.…”